rs2780956

chr9-100586352-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001018116.2(CAVIN4):c.996G>A(p.Arg332=) 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:2
• Conservation: PhyloP100: 0.338

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAVIN4	NM_001018116.2	c.996G>A	p.Arg332=	synonymous_variant	2/2	ENST00000307584.6
CAVIN4	XM_047423346.1	c.972G>A	p.Arg324=	synonymous_variant	3/3
CAVIN4	XM_047423347.1	c.609G>A	p.Arg203=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAVIN4	ENST00000307584.6	c.996G>A	p.Arg332=	synonymous_variant	2/2	1	NM_001018116.2	P1

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

GnomAD3 exomes AF: 0.379 AC: 95185 AN: 251062 Hom.: 19484 AF XY: 0.375 AC XY: 50830 AN XY: 135720

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 SAS exome AF: 0.321

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

Gnomad4 AFR exome AF: 0.274

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.426

Gnomad4 EAS exome AF: 0.0738

Gnomad4 SAS exome AF: 0.324

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.414

Gnomad4 OTH exome AF: 0.379

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

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.0911

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.379

Alfa AF: 0.403 Hom.: 4033

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.8
Dann	Benign	0.54

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

Publications

LitVar

Other links and lift over

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