rs73247430

Variant names:

• chr12-2668636-A-G
• rs73247430
• NM_000719.7:c.4624-297A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.4624-297A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00875 in 300,022 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.502
• Publications: 0 publications found

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-2668636-A-G is Benign according to our data. Variant chr12-2668636-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1199631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0149 (2267/152278) while in subpopulation AFR AF = 0.0508 (2111/41546). AF 95% confidence interval is 0.049. There are 59 homozygotes in GnomAd4. There are 1090 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2267 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4624-297A>G		intron_variant	Intron 37 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4624-297A>G		intron_variant	Intron 37 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4624-297A>G		intron_variant	Intron 37 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4624-297A>G		intron_variant	Intron 37 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4858-297A>G		intron_variant	Intron 39 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4624-297A>G		intron_variant	Intron 37 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4591-297A>G		intron_variant	Intron 36 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4789-297A>G		intron_variant	Intron 38 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4768-297A>G		intron_variant	Intron 39 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4690-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4624-297A>G		intron_variant	Intron 37 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4624-297A>G		intron_variant	Intron 37 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4714-297A>G		intron_variant	Intron 37 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4714-297A>G		intron_variant	Intron 37 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4714-297A>G		intron_variant	Intron 37 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4714-297A>G		intron_variant	Intron 37 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4708-297A>G		intron_variant	Intron 38 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4699-297A>G		intron_variant	Intron 38 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4684-297A>G		intron_variant	Intron 38 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4624-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4624-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4624-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4675-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4666-297A>G		intron_variant	Intron 37 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4591-297A>G		intron_variant	Intron 36 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4591-297A>G		intron_variant	Intron 36 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4585-297A>G		intron_variant	Intron 36 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4624-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4624-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4624-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4624-297A>G		intron_variant	Intron 37 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4624-297A>G		intron_variant	Intron 37 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4615-297A>G		intron_variant	Intron 37 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4591-297A>G		intron_variant	Intron 36 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2260 AN: 152162 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00243 AC: 359 AN: 147744 Hom.: 9 Cov.: 0 AF XY: 0.00235 AC XY: 178 AN XY: 75730

African (AFR) AF: 0.0493 AC: 259 AN: 5256

American (AMR) AF: 0.00266 AC: 18 AN: 6768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5046

East Asian (EAS) AF: 0.00 AC: 0 AN: 10220

South Asian (SAS) AF: 0.000273 AC: 3 AN: 11008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8204

Middle Eastern (MID) AF: 0.00425 AC: 3 AN: 706

European-Non Finnish (NFE) AF: 0.000263 AC: 24 AN: 91262

Other (OTH) AF: 0.00561 AC: 52 AN: 9274

GnomAD4 genome AF: 0.0149 AC: 2267 AN: 152278 Hom.: 59 Cov.: 32 AF XY: 0.0146 AC XY: 1090 AN XY: 74472

African (AFR) AF: 0.0508 AC: 2111 AN: 41546

American (AMR) AF: 0.00726 AC: 111 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0114 Hom.: 1

Bravo AF: 0.0174

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 07, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.68
PhyloP100		-0.50
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: rs73247430; hg19: chr12-2777802;