7-29096107-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031311.5(CPVL):c.399G>C(p.Met133Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000014 (0 hom.)
• Consequence: CPVL NM_031311.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

Genes affected

CPVL (HGNC:14399): (carboxypeptidase vitellogenic like) The protein encoded by this gene is a carboxypeptidase and bears strong sequence similarity to serine carboxypeptidases. Carboxypeptidases are a large class of proteases that act to cleave a single amino acid from the carboxy termini of proteins or peptides. The exact function of this protein, however, has not been determined. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20103714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPVL	NM_031311.5	c.399G>C	p.Met133Ile	missense_variant	4/13	ENST00000265394.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPVL	ENST00000265394.10	c.399G>C	p.Met133Ile	missense_variant	4/13	1	NM_031311.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459302 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

The c.399G>C (p.M133I) alteration is located in exon 4 (coding exon 3) of the CPVL gene. This alteration results from a G to C substitution at nucleotide position 399, causing the methionine (M) at amino acid position 133 to be replaced by an isoleucine (I). 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	Uncertain	0.39
BayesDel_addAF	Benign	0.0063	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.30	T;T;T;.;T;T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.036
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.5	L;L;L;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.40	T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;.;.;.
Polyphen		0.24	B;B;B;.;.;.
Vest4		0.28
MutPred		0.48		Loss of catalytic residue at V129 (P = 0.0412);Loss of catalytic residue at V129 (P = 0.0412);Loss of catalytic residue at V129 (P = 0.0412);.;.;.;
MVP		0.90
MPC		0.32
ClinPred		0.39	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.43

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: chr7-29135723;