8-61458343-C-G

Position:

• chr8-61458343-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173519.3(CLVS1):​c.778C>G​(p.Gln260Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CLVS1 NM_173519.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

Genes affected

CLVS1 (HGNC:23139): (clavesin 1) Enables phosphatidylinositol-3,5-bisphosphate binding activity. Predicted to be involved in lysosome organization. Located in endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28062987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLVS1	NM_173519.3	c.778C>G	p.Gln260Glu	missense_variant	5/6	ENST00000325897.5	NP_775790.1
CLVS1	XM_017013141.2	c.778C>G	p.Gln260Glu	missense_variant	6/7		XP_016868630.1
CLVS1	XM_017013142.3	c.778C>G	p.Gln260Glu	missense_variant	6/7		XP_016868631.1
CLVS1	XM_024447079.2	c.778C>G	p.Gln260Glu	missense_variant	8/9		XP_024302847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLVS1	ENST00000325897.5	c.778C>G	p.Gln260Glu	missense_variant	5/6	1	NM_173519.3	ENSP00000325506	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727146

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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 08, 2023

The c.778C>G (p.Q260E) alteration is located in exon 5 (coding exon 4) of the CLVS1 gene. This alteration results from a C to G substitution at nucleotide position 778, causing the glutamine (Q) at amino acid position 260 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	0.15
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.033
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.17	N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.18	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.21	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.027	B;B
Vest4		0.59
MutPred		0.38		Gain of catalytic residue at Q260 (P = 0.0172);Gain of catalytic residue at Q260 (P = 0.0172);
MVP		0.62
MPC		0.45
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.23
gMVP		0.52

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: rs977574348; hg19: chr8-62370902;