rs774660673

Variant names:

• chr16-1220242-ATCACCAGCTCCGCCT-A
• rs774660673
• NM_021098.3:c.6311_6325delTCACCAGCTCCGCCT

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4 BS1_Supporting BS2

The NM_021098.3(CACNA1H):​c.6311_6325delTCACCAGCTCCGCCT​(p.Ile2104_Cys2109delinsSer) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000379 in 1,584,744 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I2104I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1H NM_021098.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.81
• Publications: 0 publications found

Genes affected

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

CACNA1H Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021098.3.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000237 (36/152086) while in subpopulation AMR AF = 0.00216 (33/15284). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6311_6325delTCACCAGCTCCGCCT	p.Ile2104_Cys2109delinsSer	disruptive_inframe_deletion	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6311_6325delTCACCAGCTCCGCCT	p.Ile2104_Cys2109delinsSer	disruptive_inframe_deletion	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.6326_6340delTCACCAGCTCCGCCT	p.Ile2109_Cys2114delinsSer	disruptive_inframe_deletion	Exon 34 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.6296_6310delTCACCAGCTCCGCCT	p.Ile2099_Cys2104delinsSer	disruptive_inframe_deletion	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.6293_6307delTCACCAGCTCCGCCT	p.Ile2098_Cys2103delinsSer	disruptive_inframe_deletion	Exon 34 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.6293_6307delTCACCAGCTCCGCCT	p.Ile2098_Cys2103delinsSer	disruptive_inframe_deletion	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.6278_6292delTCACCAGCTCCGCCT	p.Ile2093_Cys2098delinsSer	disruptive_inframe_deletion	Exon 35 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.6272_6286delTCACCAGCTCCGCCT	p.Ile2091_Cys2096delinsSer	disruptive_inframe_deletion	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.6260_6274delTCACCAGCTCCGCCT	p.Ile2087_Cys2092delinsSer	disruptive_inframe_deletion	Exon 34 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.6254_6268delTCACCAGCTCCGCCT	p.Ile2085_Cys2090delinsSer	disruptive_inframe_deletion	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.6204_6218delTCACCAGCTCCGCCT	p.His2068_Leu2073delinsGln	disruptive_inframe_deletion	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.6153_6167delTCACCAGCTCCGCCT	p.His2051_Leu2056delinsGln	disruptive_inframe_deletion	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.6126_6140delTCACCAGCTCCGCCT	p.His2042_Leu2047delinsGln	disruptive_inframe_deletion	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000637236.3	n.*2230_*2244delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1359_*1373delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4129_*4143delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5755_*5769delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*1252_*1266delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*1170_*1184delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1890_*1904delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*978_*992delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*945_*959delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.*225_*239delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.6311_6325delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.6278_6292delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.*1427_*1441delTCACCAGCTCCGCCT		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711483.1	c.*225_*239delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.*225_*239delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3	n.*2230_*2244delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1359_*1373delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4129_*4143delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5755_*5769delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*1252_*1266delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*1170_*1184delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1890_*1904delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*978_*992delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*945_*959delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.*225_*239delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1	n.*1427_*1441delTCACCAGCTCCGCCT		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2	n.6121+190_6121+204delTCACCAGCTCCGCCT		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152086 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.0000333 AC: 7 AN: 210298 AF XY: 0.0000254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000168 AC: 24 AN: 1432658 Hom.: 0 AF XY: 0.0000140 AC XY: 10 AN XY: 712442

African (AFR) AF: 0.00 AC: 0 AN: 31278

American (AMR) AF: 0.000279 AC: 12 AN: 43050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25352

East Asian (EAS) AF: 0.00 AC: 0 AN: 37914

South Asian (SAS) AF: 0.00 AC: 0 AN: 84224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103734

Other (OTH) AF: 0.000118 AC: 7 AN: 59422

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152086 Hom.: 0 Cov.: 35 AF XY: 0.000390 AC XY: 29 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00216 AC: 33 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000204

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1

Jul 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.6311_6325del, is a complex sequence change that results in the deletion of 6 and insertion of 1 amino acid(s) in the CACNA1H protein (p.Ile2104_Cys2109delinsSer). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 529561). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

May 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 6 amino acids and in-frame insertion of 1 amino acid in a non-repeat region; In silico analysis indicates that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=77/123	disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs774660673; hg19: chr16-1270242;