rs751703046

chr9-100586276-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001018116.2(CAVIN4):c.920G>C(p.Ser307Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000795 in 1,597,514 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (2 hom.)
• Consequence: CAVIN4 NM_001018116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.24

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016578317).
• BP6: Variant 9-100586276-G-C is Benign according to our data. Variant chr9-100586276-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228863.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAVIN4	NM_001018116.2	c.920G>C	p.Ser307Thr	missense_variant	2/2	ENST00000307584.6
CAVIN4	XM_047423346.1	c.896G>C	p.Ser299Thr	missense_variant	3/3
CAVIN4	XM_047423347.1	c.533G>C	p.Ser178Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAVIN4	ENST00000307584.6	c.920G>C	p.Ser307Thr	missense_variant	2/2	1	NM_001018116.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000992 AC: 24 AN: 242044 Hom.: 1 AF XY: 0.000122 AC XY: 16 AN XY: 130702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000614

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000634

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000830 AC: 120 AN: 1445380 Hom.: 2 Cov.: 33 AF XY: 0.0000976 AC XY: 70 AN XY: 716860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000391

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000590

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 01, 2015

The p.Ser307Thr variant in MURC was identified in 1 Caucasian individual with DC M and segregated with disease in 2 affected family members (Rodriguez 2011). In vitro functional studies provide some evidence that the p.Ser307Thr variant may impact protein function (Rodriguez 2011). However, these types of assays may not accurately represent biological function. This variant has been identified in 6/13026 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org). Computational prediction tools and conservation anal ysis suggest that the p.Ser307Thr variant may not impact the protein, though thi s information is not predictive enough to rule out pathogenicity. In summary, t he clinical significance of the p.Ser307Thr variant is uncertain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 18, 2020

This variant is associated with the following publications: (PMID: 21642240) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	1.4
Dann	Benign	0.62
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.030
Sift	Benign	0.53	T
Sift4G	Benign	0.39	T
Polyphen		0.065	B
Vest4		0.027
MutPred		0.12		Loss of glycosylation at S307 (P = 0.0682);
MVP		0.092
MPC		0.035
ClinPred		0.0075	T
GERP RS		0.27
Varity_R		0.043
gMVP		0.050

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: rs751703046; hg19: chr9-103348558;