rs137921742

Positions:

• chr9-100578535-G-A
• chr9-100578535-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018116.2(CAVIN4):​c.392G>A​(p.Arg131His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,613,196 control chromosomes in the GnomAD database, including 320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (67 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (253 hom.)
• Consequence: CAVIN4 NM_001018116.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.92

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006243199).
• BP6: Variant 9-100578535-G-A is Benign according to our data. Variant chr9-100578535-G-A is described in ClinVar as [Benign]. Clinvar id is 226738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.071 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAVIN4	NM_001018116.2	c.392G>A	p.Arg131His	missense_variant	1/2	ENST00000307584.6	NP_001018126.1
CAVIN4	XM_047423346.1	c.368G>A	p.Arg123His	missense_variant	2/3		XP_047279302.1
CAVIN4	XM_047423347.1	c.21+1580G>A		intron_variant			XP_047279303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAVIN4	ENST00000307584.6	c.392G>A	p.Arg131His	missense_variant	1/2	1	NM_001018116.2	ENSP00000418668	P1

Frequencies

GnomAD3 genomes AF: 0.00808 AC: 1230 AN: 152158 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0744

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.0146 AC: 3569 AN: 244484 Hom.: 212 AF XY: 0.0107 AC XY: 1420 AN XY: 133234

Gnomad AFR exome AF: 0.00151

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00969

GnomAD4 exome AF: 0.00316 AC: 4617 AN: 1460920 Hom.: 253 Cov.: 33 AF XY: 0.00260 AC XY: 1887 AN XY: 726722

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0961

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000760

Gnomad4 NFE exome AF: 0.0000962

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00811 AC: 1235 AN: 152276 Hom.: 67 Cov.: 32 AF XY: 0.00987 AC XY: 735 AN XY: 74458

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.0746

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.000695 Hom.: 6

Bravo AF: 0.0126

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.0100 AC: 1215

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 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	Arg131His in exon 1 of MURC: This variant is not expected to have clinical signi ficance because it has been identified in 9.8% (13/132) of Mexican chromosomes f rom a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/ projects/SNP; dbSNP rs137921742). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.43
Sift	Benign	0.21	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.94
MPC		0.067
ClinPred		0.041	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.28

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: rs137921742; hg19: chr9-103340817;