rs147146258

Variant names:

• chr3-53753597-A-G
• rs147146258
• NM_000720.4:c.3761A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-53753597-A-G
• chr3-53753597-A-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001128840.3(CACNA1D):​c.3701A>G​(p.Asn1234Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000799 in 1,611,702 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1234K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (3 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 7.57
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09306714).
• BP6: Variant 3-53753597-A-G is Benign according to our data. Variant chr3-53753597-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504807.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000433 (66/152348) while in subpopulation EAS AF = 0.00116 (6/5192). AF 95% confidence interval is 0.000502. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.3761A>G	p.Asn1254Ser	missense	Exon 30 of 49	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.3701A>G	p.Asn1234Ser	missense	Exon 29 of 48	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.3701A>G	p.Asn1234Ser	missense	Exon 29 of 46	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.3761A>G	p.Asn1254Ser	missense	Exon 30 of 49	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.3701A>G	p.Asn1234Ser	missense	Exon 29 of 48	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.3761A>G	p.Asn1254Ser	missense	Exon 30 of 49	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000537 AC: 135 AN: 251494 AF XY: 0.000544

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000837 AC: 1221 AN: 1459354 Hom.: 3 Cov.: 30 AF XY: 0.000843 AC XY: 612 AN XY: 726182

African (AFR) AF: 0.000479 AC: 16 AN: 33414

American (AMR) AF: 0.000872 AC: 39 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39686

South Asian (SAS) AF: 0.000534 AC: 46 AN: 86202

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000910 AC: 1010 AN: 1109702

Other (OTH) AF: 0.00118 AC: 71 AN: 60314

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74504

African (AFR) AF: 0.000192 AC: 8 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15306

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

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5192

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	2	-	not specified (2)
-	-	1	Congenital anomaly of kidney and urinary tract (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.093	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.71	N
PhyloP100		7.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.47
Sift	Benign	0.18	T
Sift4G	Benign	0.37	T
Polyphen		0.13	B
Vest4		0.69
MVP		0.88
MPC		1.7
ClinPred		0.035	T
GERP RS		5.9
Varity_R		0.33
gMVP		0.64
Mutation Taster		=69/31	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: rs147146258; hg19: chr3-53787624;