NM_001018116.2:c.996G>A

Variant names:

• chr9-100586352-G-A
• rs2780956
• NM_001018116.2:c.996G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001018116.2(CAVIN4):​c.996G>A​(p.Arg332Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,613,218 control chromosomes in the GnomAD database, including 129,738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10826 hom., cov: 30)
  • Exomes 𝑓: 0.40 (118912 hom.)
• Consequence: CAVIN4 NM_001018116.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.338
• Publications: 15 publications found

Genes affected

CAVIN4 (HGNC:33742): (caveolae associated protein 4) This gene encodes a protein containing two coiled-coil regions. The encoded protein promotes Rho/ROCK (Rho-kinase) signaling in cardiac muscles cells, and may facilitate myofibrillar organization. [provided by RefSeq, Jun 2013]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 9-100586352-G-A is Benign according to our data. Variant chr9-100586352-G-A is described in ClinVar as Benign. ClinVar VariationId is 226743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.338 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN4	NM_001018116.2	MANE Select	c.996G>A	p.Arg332Arg	synonymous	Exon 2 of 2	NP_001018126.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN4	ENST00000307584.6	TSL:1 MANE Select	c.996G>A	p.Arg332Arg	synonymous	Exon 2 of 2	ENSP00000418668.1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55637 AN: 151482 Hom.: 10815 Cov.: 30

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.0911

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.381

GnomAD2 exomes AF: 0.379 AC: 95185 AN: 251062 AF XY: 0.375

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.0872

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.397 AC: 580482 AN: 1461614 Hom.: 118912 Cov.: 42 AF XY: 0.395 AC XY: 287097 AN XY: 727090

African (AFR) AF: 0.274 AC: 9161 AN: 33478

American (AMR) AF: 0.511 AC: 22864 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 11135 AN: 26126

East Asian (EAS) AF: 0.0738 AC: 2929 AN: 39696

South Asian (SAS) AF: 0.324 AC: 27967 AN: 86198

European-Finnish (FIN) AF: 0.402 AC: 21444 AN: 53380

Middle Eastern (MID) AF: 0.326 AC: 1880 AN: 5764

European-Non Finnish (NFE) AF: 0.414 AC: 460185 AN: 1111870

Other (OTH) AF: 0.379 AC: 22917 AN: 60388

GnomAD4 genome AF: 0.367 AC: 55700 AN: 151604 Hom.: 10826 Cov.: 30 AF XY: 0.367 AC XY: 27197 AN XY: 74100

African (AFR) AF: 0.282 AC: 11646 AN: 41282

American (AMR) AF: 0.449 AC: 6840 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3466

East Asian (EAS) AF: 0.0911 AC: 469 AN: 5148

South Asian (SAS) AF: 0.316 AC: 1509 AN: 4780

European-Finnish (FIN) AF: 0.407 AC: 4276 AN: 10502

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.415 AC: 28143 AN: 67876

Other (OTH) AF: 0.379 AC: 795 AN: 2098

Alfa AF: 0.401 Hom.: 4071

Bravo AF: 0.365

Asia WGS AF: 0.210 AC: 730 AN: 3478

EpiCase AF: 0.413

EpiControl AF: 0.406

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Sep 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg332Arg in exon 2 of MURC: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 41.7% (3583/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2780956).

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.8
DANN	Benign	0.54
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs2780956; hg19: chr9-103348634; COSMIC: COSV56866572; COSMIC: COSV56866572;