rs752555064

chr8-67483815-C-Achr8-67483815-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020361.5(CPA6):c.791G>T(p.Arg264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R264H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CPA6 NM_020361.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16373497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPA6	NM_020361.5	c.791G>T	p.Arg264Leu	missense_variant	8/11	ENST00000297770.10
ARFGEF1-DT	NR_136224.1	n.694-7150C>A		intron_variant, non_coding_transcript_variant
CPA6	XM_017013646.2	c.347G>T	p.Arg116Leu	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA6	ENST00000297770.10	c.791G>T	p.Arg264Leu	missense_variant	8/11	1	NM_020361.5	P1
CPA6	ENST00000518549.1	n.1005G>T		non_coding_transcript_exon_variant	8/8	1
CPA6	ENST00000479862.6	c.*387G>T		3_prime_UTR_variant, NMD_transcript_variant	7/8	1
CPA6	ENST00000638254.1	c.*387G>T		3_prime_UTR_variant, NMD_transcript_variant	7/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251454 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	12
Dann	Benign	0.69
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.30	N
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.073
Sift	Benign	0.29	T
Sift4G	Benign	0.74	T
Polyphen		0.0020	B
Vest4		0.57
MutPred		0.46		Loss of disorder (P = 0.0255);
MVP		0.15
MPC		0.044
ClinPred		0.33	T
GERP RS		-2.9
Varity_R		0.14
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs752555064; hg19: chr8-68396050;