chr2-191836684-T-C

Position:

• chr2-191836684-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004657.6(CAVIN2):​c.517A>G​(p.Lys173Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAVIN2 NM_004657.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

CAVIN2 (HGNC:10690): (caveolae associated protein 2) This gene encodes a calcium-independent phospholipid-binding protein whose expression increases in serum-starved cells. This protein is a substrate for protein kinase C (PKC) phosphorylation and recruits polymerase I and transcript release factor (PTRF) to caveolae. Removal of this protein causes caveolae loss and its over-expression results in caveolae deformation and membrane tubulation.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAVIN2	NM_004657.6	c.517A>G	p.Lys173Glu	missense_variant	2/2	ENST00000304141.5	NP_004648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAVIN2	ENST00000304141.5	c.517A>G	p.Lys173Glu	missense_variant	2/2	1	NM_004657.6	ENSP00000305675	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461528 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727032

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

The c.517A>G (p.K173E) alteration is located in exon 2 (coding exon 2) of the SDPR gene. This alteration results from a A to G substitution at nucleotide position 517, causing the lysine (K) at amino acid position 173 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	-0.023	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.021	D
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.53
MutPred		0.44		Gain of helix (P = 0.0022);
MVP		0.65
MPC		1.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.42
gMVP		0.20

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: rs1690027182; hg19: chr2-192701410; COSMIC: COSV100414413;