7-81950198-C-A

Variant names:

• chr7-81950198-C-A
• rs75370027
• NM_000722.4:c.*194G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000722.4(CACNA2D1):​c.*194G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 886,172 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: CACNA2D1 NM_000722.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.234
• Publications: 1 publications found

Genes affected

CACNA2D1 (HGNC:1399): (calcium voltage-gated channel auxiliary subunit alpha2delta 1) The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

CACNA2D1 Gene-Disease associations (from GenCC):

• short QT syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• developmental and epileptic encephalopathy 110

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Brugada syndrome

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 7-81950198-C-A is Benign according to our data. Variant chr7-81950198-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1316305.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00478 (728/152142) while in subpopulation AFR AF = 0.0168 (698/41530). AF 95% confidence interval is 0.0158. There are 9 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000722.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.*194G>T		3_prime_UTR	Exon 39 of 39	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.*194G>T		3_prime_UTR	Exon 39 of 39	NP_001353796.1	P54289-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.*194G>T		3_prime_UTR	Exon 39 of 39	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.*194G>T		3_prime_UTR	Exon 39 of 39	ENSP00000409374.2	H0Y715
	CACNA2D1	ENST00000957014.1		c.*194G>T		3_prime_UTR	Exon 39 of 39	ENSP00000627073.1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 728 AN: 152024 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000499 AC: 366 AN: 734030 Hom.: 1 Cov.: 10 AF XY: 0.000422 AC XY: 159 AN XY: 376840

African (AFR) AF: 0.0161 AC: 301 AN: 18666

American (AMR) AF: 0.00103 AC: 26 AN: 25310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16470

East Asian (EAS) AF: 0.00 AC: 0 AN: 33184

South Asian (SAS) AF: 0.00 AC: 0 AN: 54684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2560

European-Non Finnish (NFE) AF: 0.0000175 AC: 9 AN: 515252

Other (OTH) AF: 0.000845 AC: 30 AN: 35496

GnomAD4 genome AF: 0.00479 AC: 728 AN: 152142 Hom.: 9 Cov.: 32 AF XY: 0.00460 AC XY: 342 AN XY: 74374

African (AFR) AF: 0.0168 AC: 698 AN: 41530

American (AMR) AF: 0.00170 AC: 26 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67978

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.00550

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.84
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism

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: rs75370027; hg19: chr7-81579514;