3-53494986-T-A

Variant names:

• chr3-53494986-T-A
• rs312479
• NM_000720.4:c.-181T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128840.3(CACNA1D):​c.-181T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 401,344 control chromosomes in the GnomAD database, including 176,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67035 hom., cov: 26)
  • Exomes 𝑓: 0.93 (108978 hom.)
• Consequence: CACNA1D NM_001128840.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.67

Genes affected

CACNA1D (HGNC:1391): (calcium voltage-gated channel subunit alpha1 D) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-53494986-T-A is Benign according to our data. Variant chr3-53494986-T-A is described in ClinVar as [Benign]. Clinvar id is 1260477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.-181T>A		5_prime_UTR_variant	Exon 1 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.-181T>A		5_prime_UTR_variant	Exon 1 of 48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139	c.-181T>A		5_prime_UTR_variant	Exon 1 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061	c.-181T>A		5_prime_UTR_variant	Exon 1 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.943 AC: 141966 AN: 150572 Hom.: 66987 Cov.: 26

Gnomad AFR AF: 0.967

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.954

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.976

Gnomad FIN AF: 0.966

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.915

Gnomad OTH AF: 0.949

GnomAD4 exome AF: 0.930 AC: 233235 AN: 250672 Hom.: 108978 Cov.: 3 AF XY: 0.933 AC XY: 126306 AN XY: 135334

Gnomad4 AFR exome AF: 0.965

Gnomad4 AMR exome AF: 0.958

Gnomad4 ASJ exome AF: 0.942

Gnomad4 EAS exome AF: 0.997

Gnomad4 SAS exome AF: 0.972

Gnomad4 FIN exome AF: 0.959

Gnomad4 NFE exome AF: 0.904

Gnomad4 OTH exome AF: 0.930

GnomAD4 genome AF: 0.943 AC: 142064 AN: 150672 Hom.: 67035 Cov.: 26 AF XY: 0.948 AC XY: 69639 AN XY: 73486

Gnomad4 AFR AF: 0.967

Gnomad4 AMR AF: 0.954

Gnomad4 ASJ AF: 0.950

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.976

Gnomad4 FIN AF: 0.966

Gnomad4 NFE AF: 0.915

Gnomad4 OTH AF: 0.950

Alfa AF: 0.930 Hom.: 8181

Bravo AF: 0.942

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.9
DANN	Benign	0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs312479; hg19: chr3-53529013;