chr3-53769994-C-T

Variant names:

• chr3-53769994-C-T
• rs72556360
• NM_000720.4:c.3952C>T

Variant summary

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

The NM_001128840.3(CACNA1D):​c.3892C>T​(p.Pro1298Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00594 in 1,613,132 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1298R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (40 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.60
• Publications: 8 publications found

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]

CACNA1D Gene-Disease associations (from GenCC):

• aldosterone-producing adenoma with seizures and neurological abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• sinoatrial node dysfunction and deafness

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057592094).
• BP6: Variant 3-53769994-C-T is Benign according to our data. Variant chr3-53769994-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00513 (781/152304) while in subpopulation NFE AF = 0.00536 (365/68034). AF 95% confidence interval is 0.00491. There are 6 homozygotes in GnomAd4. There are 461 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128840.3. 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
	CACNA1D	NM_000720.4	MANE Plus Clinical	c.3952C>T	p.Pro1318Ser	missense	Exon 32 of 49	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.3892C>T	p.Pro1298Ser	missense	Exon 31 of 48	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.3871-430C>T		intron	N/A	NP_001122311.1	Q01668-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1D	ENST00000288139.11	TSL:1 MANE Plus Clinical	c.3952C>T	p.Pro1318Ser	missense	Exon 32 of 49	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.3892C>T	p.Pro1298Ser	missense	Exon 31 of 48	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.3952C>T	p.Pro1318Ser	missense	Exon 32 of 49	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 781 AN: 152186 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00536

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00519 AC: 1305 AN: 251464 AF XY: 0.00514

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0268

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00603 AC: 8803 AN: 1460828 Hom.: 40 Cov.: 30 AF XY: 0.00592 AC XY: 4306 AN XY: 726828

African (AFR) AF: 0.00108 AC: 36 AN: 33464

American (AMR) AF: 0.00114 AC: 51 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86236

European-Finnish (FIN) AF: 0.0243 AC: 1299 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00630 AC: 7000 AN: 1111058

Other (OTH) AF: 0.00550 AC: 332 AN: 60348

GnomAD4 genome AF: 0.00513 AC: 781 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00619 AC XY: 461 AN XY: 74472

African (AFR) AF: 0.000914 AC: 38 AN: 41558

American (AMR) AF: 0.00320 AC: 49 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0295 AC: 313 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00536 AC: 365 AN: 68034

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00504 Hom.: 6

Bravo AF: 0.00345

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00481 AC: 584

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00539

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Aldosterone-producing adenoma with seizures and neurological abnormalities (1)
-	-	1	CACNA1D-related disorder (1)
-	-	1	Sinoatrial node dysfunction and deafness;C3809609:Aldosterone-producing adenoma with seizures and neurological abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Benign	0.19
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0058	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.23	N
PhyloP100		3.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.26	N
REVEL	Uncertain	0.38
Sift	Benign	0.90	T
Sift4G	Benign	0.91	T
Polyphen		0.0010	B
Vest4		0.36
MVP		0.81
MPC		0.81
ClinPred		0.021	T
GERP RS		5.9
Varity_R		0.077
gMVP		0.40
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72556360; hg19: chr3-53804021; COSMIC: COSV55448703; COSMIC: COSV55448703;