rs781369203

Variant names:

• chr8-67483849-A-C
• rs781369203
• NM_020361.5:c.757T>G
• CPA6 p.Trp253Gly

Your query was ambiguous. Multiple possible variants found:

• chr8-67483849-A-C
• chr8-67483849-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020361.5(CPA6):​c.757T>G​(p.Trp253Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. W253R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPA6 NM_020361.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.83
• Publications: 0 publications found

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:55237): (ARFGEF1 divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020361.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA6	NM_020361.5	MANE Select	c.757T>G	p.Trp253Gly	missense	Exon 8 of 11	NP_065094.3
	ARFGEF1-DT	NR_136224.1		n.694-7116A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA6	ENST00000297770.10	TSL:1 MANE Select	c.757T>G	p.Trp253Gly	missense	Exon 8 of 11	ENSP00000297770.4	Q8N4T0-1
	CPA6	ENST00000479862.6	TSL:1	n.*353T>G		non_coding_transcript_exon	Exon 7 of 8	ENSP00000419016.2	Q8N4T0-3
	CPA6	ENST00000518549.1	TSL:1	n.971T>G		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461368 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111550

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial temporal lobe epilepsy 5;C3280734:Febrile seizures, familial, 11 (1)
-	1	-	Febrile seizures, familial, 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-12	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.95
gMVP		0.97
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs781369203;

hg19: chr8-68396084;