rs116000902

chr9-100578557-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001018116.2(CAVIN4):c.408+6C>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,612,612 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (7 hom.)
• Consequence: CAVIN4 NM_001018116.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001256
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.270

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 9-100578557-C-A is Benign according to our data. Variant chr9-100578557-C-A is described in ClinVar as [Benign]. Clinvar id is 390964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00579 (881/152276) while in subpopulation AFR AF= 0.02 (833/41548). AF 95% confidence interval is 0.0189. There are 8 homozygotes in gnomad4. There are 403 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAVIN4	NM_001018116.2	c.408+6C>A		splice_donor_region_variant, intron_variant		ENST00000307584.6
CAVIN4	XM_047423346.1	c.384+6C>A		splice_donor_region_variant, intron_variant
CAVIN4	XM_047423347.1	c.21+1602C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAVIN4	ENST00000307584.6	c.408+6C>A		splice_donor_region_variant, intron_variant		1	NM_001018116.2	P1

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 882 AN: 152158 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

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: 0.000118

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00160 AC: 389 AN: 242746 Hom.: 1 AF XY: 0.00120 AC XY: 159 AN XY: 132572

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.000408

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000652

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.000589 AC: 860 AN: 1460336 Hom.: 7 Cov.: 33 AF XY: 0.000496 AC XY: 360 AN XY: 726434

Gnomad4 AFR exome AF: 0.0203

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00579 AC: 881 AN: 152276 Hom.: 8 Cov.: 32 AF XY: 0.00541 AC XY: 403 AN XY: 74442

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00327 Hom.: 3

Bravo AF: 0.00636

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	408+6C>A in intron 1 of MURC: This variant is not expected to have clinical sign ificance because it has been identified in 1.8% (77/4394) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs116000902). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2017	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
BayesDel_noAF	Benign	-0.34
Cadd	Benign	8.7
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.020
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: rs116000902; hg19: chr9-103340839;