rs114402678

Variant names:

• chr8-67483797-G-A
• rs114402678
• NM_020361.5:c.809C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_020361.5(CPA6):​c.809C>T​(p.Ala270Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000553 in 1,614,054 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A270A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: CPA6 NM_020361.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:3
• Conservation: PhyloP100: 9.48
• Publications: 11 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019862473).
• BP6: Variant 8-67483797-G-A is Benign according to our data. Variant chr8-67483797-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30791.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA6	NM_020361.5	MANE Select	c.809C>T	p.Ala270Val	missense	Exon 8 of 11	NP_065094.3
	ARFGEF1-DT	NR_136224.1		n.694-7168G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA6	ENST00000297770.10	TSL:1 MANE Select	c.809C>T	p.Ala270Val	missense	Exon 8 of 11	ENSP00000297770.4
	CPA6	ENST00000479862.6	TSL:1	n.*405C>T		non_coding_transcript_exon	Exon 7 of 8	ENSP00000419016.2
	CPA6	ENST00000518549.1	TSL:1	n.1023C>T		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152102 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00949

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000736 AC: 185 AN: 251474 AF XY: 0.000552

Gnomad AFR exome AF: 0.00904

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000315 AC: 460 AN: 1461834 Hom.: 0 Cov.: 30 AF XY: 0.000281 AC XY: 204 AN XY: 727220

African (AFR) AF: 0.00971 AC: 325 AN: 33478

American (AMR) AF: 0.000939 AC: 42 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111960

Other (OTH) AF: 0.000679 AC: 41 AN: 60392

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152220 Hom.: 2 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74444

African (AFR) AF: 0.00953 AC: 396 AN: 41540

American (AMR) AF: 0.00190 AC: 29 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000927 Hom.: 3

Bravo AF: 0.00332

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	1	Febrile seizures, familial, 11 (3)
-	-	1	CPA6-related disorder (1)
-	-	1	Familial temporal lobe epilepsy 5 (1)
-	1	-	Intellectual disability (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.30
Sift	Benign	0.32	T
Sift4G	Benign	0.24	T
Polyphen		0.95	P
Vest4		0.87
MVP		0.52
MPC		0.24
ClinPred		0.041	T
GERP RS		5.2
Varity_R		0.49
gMVP		0.83
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114402678; hg19: chr8-68396032;