16-1220184-G-C

Variant names:

• chr16-1220184-G-C
• rs767753103
• ENST00000711482.1:c.6145G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000711482.1(CACNA1H):​c.6145G>C​(p.Gly2049Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2049D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 35)
• Consequence: CACNA1H ENST00000711482.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.780
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6252G>C	p.Ala2084Ala	synonymous_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000711482.1	c.6145G>C	p.Gly2049Arg	missense_variant	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.6094G>C	p.Gly2032Arg	missense_variant	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.6067G>C	p.Gly2023Arg	missense_variant	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000348261.11	c.6252G>C	p.Ala2084Ala	synonymous_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.6267G>C	p.Ala2089Ala	synonymous_variant	Exon 34 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.6237G>C	p.Ala2079Ala	synonymous_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.6234G>C	p.Ala2078Ala	synonymous_variant	Exon 34 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.6234G>C	p.Ala2078Ala	synonymous_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.6219G>C	p.Ala2073Ala	synonymous_variant	Exon 35 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.6213G>C	p.Ala2071Ala	synonymous_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.6201G>C	p.Ala2067Ala	synonymous_variant	Exon 34 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.6195G>C	p.Ala2065Ala	synonymous_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000637236.3	n.*2171G>C		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1300G>C		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4070G>C		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5696G>C		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*1193G>C		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*1111G>C		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1831G>C		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*919G>C		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*886G>C		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.*166G>C		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.6252G>C		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.6219G>C		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.*1368G>C		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711483.1	c.*166G>C		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.*166G>C		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3	n.*2171G>C		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1300G>C		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4070G>C		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5696G>C		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*1193G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*1111G>C		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1831G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*919G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*886G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.*166G>C		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1	n.*1368G>C		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2	n.6121+131G>C		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 72

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.046
DANN	Benign	0.45
PhyloP100		-0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs767753103; hg19: chr16-1270184;