rs10957393

Positions:

• chr8-67624235-A-C
• chr8-67624235-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000297770.10(CPA6):​c.133T>G​(p.Phe45Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F45L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPA6 ENST00000297770.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05

Genes affected

CPA6 (HGNC:17245): (carboxypeptidase A6) The gene encodes a member of the peptidase M14 family of metallocarboxypeptidases. The encoded preproprotein is proteolytically processed to generate the mature enzyme, which catalyzes the release of large hydrophobic C-terminal amino acids. This enzyme has functions ranging from digestion of food to selective biosynthesis of neuroendocrine peptides. Mutations in this gene may be linked to epilepsy and febrile seizures, and a translocation t(6;8)(q26;q13) involving this gene has been associated with Duane retraction syndrome. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05220884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPA6	NM_020361.5	c.133T>G	p.Phe45Val	missense_variant	2/11	ENST00000297770.10	NP_065094.3
CPA6	XM_017013647.2	c.133T>G	p.Phe45Val	missense_variant	2/7		XP_016869136.1
CPA6	XM_017013646.2	c.-187T>G		5_prime_UTR_variant	3/11		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10	c.133T>G	p.Phe45Val	missense_variant	2/11	1	NM_020361.5	ENSP00000297770	P1
CPA6	ENST00000518549.1	n.347T>G		non_coding_transcript_exon_variant	2/8	1
CPA6	ENST00000479862.6	c.133T>G	p.Phe45Val	missense_variant, NMD_transcript_variant	2/8	1		ENSP00000419016
CPA6	ENST00000638254.1	c.133T>G	p.Phe45Val	missense_variant, NMD_transcript_variant	2/10	5		ENSP00000491129

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.30
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
MutationTaster	Benign	0.99	P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.35		Gain of ubiquitination at K48 (P = 0.0898);
MVP		0.20
MPC		0.035
ClinPred		0.098	T
GERP RS		4.5
Varity_R		0.071
gMVP		0.47

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: rs10957393; hg19: chr8-68536470;