8-67422613-G-T

Variant summary

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

The NM_020361.5(CPA6):c.1205C>A(p.Thr402Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPA6 NM_020361.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.57

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]

ARFGEF1-DT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPA6	NM_020361.5	c.1205C>A	p.Thr402Asn	missense_variant	11/11	ENST00000297770.10
ARFGEF1-DT	NR_136224.1	n.470-19597G>T		intron_variant, non_coding_transcript_variant
CPA6	XM_017013646.2	c.761C>A	p.Thr254Asn	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA6	ENST00000297770.10	c.1205C>A	p.Thr402Asn	missense_variant	11/11	1	NM_020361.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial temporal lobe epilepsy 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.1205C>A p.Thr402Asn variant in CPA6 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Thr402Asn variant is novel not in any individuals in both gnomAD Exomes and 1000 Genomes databases. This variant has not been reported to the ClinVar database. The amino acid change p.Thr402Asn in CPA6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 402 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.014	D
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.55		Loss of sheet (P = 0.1158);
MVP		0.58
MPC		0.25
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.62
gMVP		0.94

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: chr8-68334848;