rs35131433

Variant names:

• chr7-81959300-T-G
• rs35131433
• NM_000722.4:c.3134A>C
• CACNA2D1 p.Asp1045Ala

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000722.4(CACNA2D1):​c.3134A>C​(p.Asp1045Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0052 in 1,610,030 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts 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. D1045N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (36 hom.)
• Consequence: CACNA2D1 NM_000722.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.63
• Publications: 13 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: Orphanet, ClinGen
• Brugada syndrome

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009257674).
• BP6: Variant 7-81959300-T-G is Benign according to our data. Variant chr7-81959300-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown,AD 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.3134A>C	p.Asp1045Ala	missense	Exon 38 of 39	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.3170A>C	p.Asp1057Ala	missense	Exon 38 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.3134A>C	p.Asp1045Ala	missense	Exon 38 of 39	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.3170A>C	p.Asp1057Ala	missense	Exon 38 of 39	ENSP00000409374.2	H0Y715
	CACNA2D1	ENST00000957014.1		c.3155A>C	p.Asp1052Ala	missense	Exon 38 of 39	ENSP00000627073.1

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 550 AN: 152052 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00680

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00299 AC: 749 AN: 250800 AF XY: 0.00306

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00550

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00536 AC: 7821 AN: 1457860 Hom.: 36 Cov.: 28 AF XY: 0.00521 AC XY: 3778 AN XY: 725500

African (AFR) AF: 0.00102 AC: 34 AN: 33396

American (AMR) AF: 0.000784 AC: 35 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86194

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53374

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.00670 AC: 7428 AN: 1108514

Other (OTH) AF: 0.00339 AC: 204 AN: 60232

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152170 Hom.: 2 Cov.: 32 AF XY: 0.00323 AC XY: 240 AN XY: 74382

African (AFR) AF: 0.00123 AC: 51 AN: 41574

American (AMR) AF: 0.00118 AC: 18 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00680 AC: 462 AN: 67966

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00509 Hom.: 10

Bravo AF: 0.00339

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00568

EpiControl AF: 0.00510

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Varity_R		0.33
gMVP		0.84
Mutation Taster		=62/38	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35131433;

hg19: chr7-81588616;

COSMIC: COSV99070867;

COSMIC: COSV99070867;