9-100578376-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018116.2(CAVIN4):c.233C>T(p.Ser78Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00125 in 1,613,944 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (10 hom.)
• Consequence: CAVIN4 NM_001018116.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.93

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=0.010524869).
• BP6: Variant 9-100578376-C-T is Benign according to our data. Variant chr9-100578376-C-T is described in ClinVar as [Benign]. Clinvar id is 226739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100578376-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00646 (983/152136) while in subpopulation AFR AF= 0.0228 (945/41494). AF 95% confidence interval is 0.0216. There are 7 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAVIN4	NM_001018116.2	c.233C>T	p.Ser78Leu	missense_variant	1/2	ENST00000307584.6
CAVIN4	XM_047423346.1	c.209C>T	p.Ser70Leu	missense_variant	2/3
CAVIN4	XM_047423347.1	c.21+1421C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAVIN4	ENST00000307584.6	c.233C>T	p.Ser78Leu	missense_variant	1/2	1	NM_001018116.2	P1

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 981 AN: 152018 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00163 AC: 410 AN: 251236 Hom.: 2 AF XY: 0.00117 AC XY: 159 AN XY: 135752

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000703 AC: 1027 AN: 1461808 Hom.: 10 Cov.: 33 AF XY: 0.000579 AC XY: 421 AN XY: 727214

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00646 AC: 983 AN: 152136 Hom.: 7 Cov.: 32 AF XY: 0.00633 AC XY: 471 AN XY: 74372

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00130 Hom.: 5

Bravo AF: 0.00736

ESP6500AA AF: 0.0227 AC: 100

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser78Leu in exon 1 of MURC: This variant is not expected to have clinical signif icance because it has been identified in 2.3% (100/4406) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs73657328). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.67	N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Benign	0.13	T
Polyphen		0.89	P
Vest4		0.34
MVP		0.49
MPC		0.052
ClinPred		0.026	T
GERP RS		4.1
Varity_R		0.20
gMVP		0.15

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: rs73657328; hg19: chr9-103340658; COSMIC: COSV99059093; COSMIC: COSV99059093;