9-100578281-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001018116.2(CAVIN4):c.138T>G(p.Ser46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAVIN4 NM_001018116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.11

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03921768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAVIN4	NM_001018116.2	c.138T>G	p.Ser46Arg	missense_variant	1/2	ENST00000307584.6
CAVIN4	XM_047423346.1	c.114T>G	p.Ser38Arg	missense_variant	2/3
CAVIN4	XM_047423347.1	c.21+1326T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAVIN4	ENST00000307584.6	c.138T>G	p.Ser46Arg	missense_variant	1/2	1	NM_001018116.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 15, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	4.6
Dann	Benign	0.94
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.78	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.099
Sift	Benign	0.081	T
Sift4G	Benign	0.097	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.21		Gain of MoRF binding (P = 0.0081);
MVP		0.18
MPC		0.041
ClinPred		0.11	T
GERP RS		-5.4
Varity_R		0.15
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-103340563;