rs3395

Variant names:

• chr8-67422176-T-C
• rs3395
• NM_020361.5:c.*328A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020361.5(CPA6):​c.*328A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 208,222 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (86 hom., cov: 32)
  • Exomes 𝑓: 0.029 (39 hom.)
• Consequence: CPA6 NM_020361.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.74
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-67422176-T-C is Benign according to our data. Variant chr8-67422176-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 363596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0281 (4280/152290) while in subpopulation NFE AF = 0.043 (2927/68028). AF 95% confidence interval is 0.0417. There are 86 homozygotes in GnomAd4. There are 1941 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 86 AR,AD gene

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.*328A>G		3_prime_UTR	Exon 11 of 11	NP_065094.3
	ARFGEF1-DT	NR_136224.1		n.470-20034T>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.*328A>G		3_prime_UTR	Exon 11 of 11	ENSP00000297770.4	Q8N4T0-1
	CPA6	ENST00000479862.6	TSL:1	n.*950A>G		non_coding_transcript_exon	Exon 8 of 8	ENSP00000419016.2	Q8N4T0-3
	CPA6	ENST00000479862.6	TSL:1	n.*950A>G		3_prime_UTR	Exon 8 of 8	ENSP00000419016.2	Q8N4T0-3

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4279 AN: 152172 Hom.: 86 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0430

Gnomad OTH AF: 0.0344

GnomAD4 exome AF: 0.0292 AC: 1634 AN: 55932 Hom.: 39 Cov.: 0 AF XY: 0.0288 AC XY: 820 AN XY: 28448

African (AFR) AF: 0.00665 AC: 15 AN: 2254

American (AMR) AF: 0.0213 AC: 67 AN: 3144

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 47 AN: 2212

East Asian (EAS) AF: 0.00 AC: 0 AN: 4254

South Asian (SAS) AF: 0.00637 AC: 11 AN: 1728

European-Finnish (FIN) AF: 0.0202 AC: 43 AN: 2132

Middle Eastern (MID) AF: 0.0236 AC: 6 AN: 254

European-Non Finnish (NFE) AF: 0.0368 AC: 1337 AN: 36310

Other (OTH) AF: 0.0296 AC: 108 AN: 3644

GnomAD4 genome AF: 0.0281 AC: 4280 AN: 152290 Hom.: 86 Cov.: 32 AF XY: 0.0261 AC XY: 1941 AN XY: 74458

African (AFR) AF: 0.00664 AC: 276 AN: 41568

American (AMR) AF: 0.0283 AC: 433 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4822

European-Finnish (FIN) AF: 0.0281 AC: 298 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0430 AC: 2927 AN: 68028

Other (OTH) AF: 0.0341 AC: 72 AN: 2114

Alfa AF: 0.0384 Hom.: 282

Bravo AF: 0.0278

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial temporal lobe epilepsy 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.045
DANN	Benign	0.45
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3395; hg19: chr8-68334411;