8-96785082-G-A

Variant summary

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

The NM_016134.4(CPQ):c.185G>A(p.Arg62Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,590 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: 6.8e-7 (0 hom.)
• Consequence: CPQ NM_016134.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31

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]

LOC124901985 (HGNC:):

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=0.3492651).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPQ	NM_016134.4	c.185G>A	p.Arg62Lys	missense_variant	2/8	ENST00000220763.10
LOC124901985	XR_007061019.1	n.354+6460C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPQ	ENST00000220763.10	c.185G>A	p.Arg62Lys	missense_variant	2/8	1	NM_016134.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 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

May 11, 2022

The c.185G>A (p.R62K) alteration is located in exon 2 (coding exon 1) of the CPQ gene. This alteration results from a G to A substitution at nucleotide position 185, causing the arginine (R) at amino acid position 62 to be replaced by a lysine (K). 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	0.18
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0013	T;T;T;T;.
Eigen	Benign	-0.047
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.44	N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.39	T;T;T;T;T
Sift4G	Benign	0.85	T;D;T;T;D
Polyphen		0.13	B;.;.;.;.
Vest4		0.79
MutPred		0.46		Gain of ubiquitination at R62 (P = 0.017);Gain of ubiquitination at R62 (P = 0.017);Gain of ubiquitination at R62 (P = 0.017);Gain of ubiquitination at R62 (P = 0.017);Gain of ubiquitination at R62 (P = 0.017);
MVP		0.27
MPC		0.12
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.29
gMVP		0.72

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: chr8-97797310;