Genetic Variant CPQ:p.Ile36Met (chr8-96785005-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016134.4(CPQ):c.108A>G(p.Ile36Met) 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 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I36V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CPQ
NM_016134.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.262

Publications

0 publications found

Variant links:

Genes affected

CPQ (HGNC:16910): (carboxypeptidase Q) This gene encodes a metallopeptidase that belongs to the peptidase M28 family. The encoded protein may catalyze the cleavage of dipeptides with unsubstituted terminals into amino acids. [provided by RefSeq, Jul 2013]

CPQ links:

LOC124901985 (HGNC:):

LOC124901985 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16619197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPQ	NM_016134.4 link	c.108A>G	p.Ile36Met	missense_variant	Exon 2 of 8	ENST00000220763.10	NP_057218.1	Q9Y646A0A024R9B8
LOC124901985	XR_007061019.1 link	n.354+6537T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPQ	ENST00000220763.10 link	c.108A>G	p.Ile36Met	missense_variant	Exon 2 of 8	1	NM_016134.4	ENSP00000220763.5		Q9Y646

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727074

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111790

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.108A>G (p.I36M) alteration is located in exon 2 (coding exon 1) of the CPQ gene. This alteration results from a A to G substitution at nucleotide position 108, causing the isoleucine (I) at amino acid position 36 to be replaced by a methionine (M). 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

0.071

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

2.7

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0063

T;T;T;T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.62

T;T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.6

M;.;.;.;.

PhyloP100

-0.26

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.69

N;N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.011

D;D;D;D;D

Sift4G

Uncertain

0.024

D;D;D;D;D

Polyphen

0.98

D;.;.;.;.

Vest4

0.21

MutPred

0.23

Loss of methylation at K37 (P = 0.0499);Loss of methylation at K37 (P = 0.0499);Loss of methylation at K37 (P = 0.0499);Loss of methylation at K37 (P = 0.0499);Loss of methylation at K37 (P = 0.0499);

MVP

0.38

MPC

0.13

ClinPred

0.79

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

gMVP

0.77

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over