rs149165620

Variant names:

• chr9-100578386-T-G
• rs149165620
• NM_001018116.2:c.243T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001018116.2(CAVIN4):​c.243T>G​(p.Asn81Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N81D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: CAVIN4 NM_001018116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.486
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019414634).
• BP6: Variant 9-100578386-T-G is Benign according to our data. Variant chr9-100578386-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227557.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN4	NM_001018116.2	MANE Select	c.243T>G	p.Asn81Lys	missense	Exon 1 of 2	NP_001018126.1	Q5BKX8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN4	ENST00000307584.6	TSL:1 MANE Select	c.243T>G	p.Asn81Lys	missense	Exon 1 of 2	ENSP00000418668.1	Q5BKX8
	CAVIN4	ENST00000956994.1		c.243T>G	p.Asn81Lys	missense	Exon 1 of 2	ENSP00000627053.1

Frequencies

GnomAD3 genomes AF: 0.000960 AC: 146 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 251222 AF XY: 0.000192

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000711 AC: 104 AN: 1461836 Hom.: 0 Cov.: 33 AF XY: 0.0000578 AC XY: 42 AN XY: 727222

African (AFR) AF: 0.00287 AC: 96 AN: 33472

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111968

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74454

African (AFR) AF: 0.00349 AC: 145 AN: 41544

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000301 Hom.: 0

Bravo AF: 0.00112

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000338 AC: 41

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.89	T
PhyloP100		-0.49
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.16
Sift	Benign	0.034	D
Sift4G	Benign	0.068	T
Polyphen		0.76	P
Vest4		0.78
MutPred		0.27		Gain of catalytic residue at N81 (P = 0.009)
MVP		0.22
MPC		0.13
ClinPred		0.095	T
GERP RS		-4.8
PromoterAI		0.019	Neutral
Varity_R		0.20
gMVP		0.18
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs149165620; hg19: chr9-103340668;