7-154052878-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_130797.4(DPP6):c.58G>A(p.Ala20Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,534,558 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: DPP6 NM_130797.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.14

Genes affected

DPP6 (HGNC:3010): (dipeptidyl peptidase like 6) This gene encodes a single-pass type II membrane protein that is a member of the peptidase S9B family of serine proteases. This protein has no detectable protease activity, most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it does bind specific voltage-gated potassium channels and alters their expression and biophysical properties. Variations in this gene may be associated with susceptibility to amyotrophic lateral sclerosis and with idiopathic ventricular fibrillation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018543452).
• BS2: High AC in GnomAd at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPP6	NM_130797.4	c.58G>A	p.Ala20Thr	missense_variant	1/26	ENST00000377770.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPP6	ENST00000377770.8	c.58G>A	p.Ala20Thr	missense_variant	1/26	1	NM_130797.4
DPP6	ENST00000406326.5	c.58G>A	p.Ala20Thr	missense_variant	1/6	1
DPP6	ENST00000404039.5	c.51+165144G>A		intron_variant		1
DPP6	ENST00000706130.1	c.60+303870G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.000251 AC: 38 AN: 151308 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000294 AC: 406 AN: 1383250 Hom.: 1 Cov.: 43 AF XY: 0.000305 AC XY: 208 AN XY: 682648

Gnomad4 AFR exome AF: 0.0000325

Gnomad4 AMR exome AF: 0.000538

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.0000571

Gnomad4 SAS exome AF: 0.0000506

Gnomad4 FIN exome AF: 0.0000237

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.000314

GnomAD4 genome AF: 0.000251 AC: 38 AN: 151308 Hom.: 0 Cov.: 31 AF XY: 0.000244 AC XY: 18 AN XY: 73886

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000400 Hom.: 0

ExAC AF: 0.0000425 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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- -

Ventricular fibrillation, paroxysmal familial, 2;C4225375:Intellectual disability, autosomal dominant 33 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.51	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.045
Sift	Uncertain	0.0090	D;T
Sift4G	Benign	0.083	T;T
Polyphen		0.95	P;B
Vest4		0.062
MVP		0.082
MPC		0.40
ClinPred		0.066	T
GERP RS		2.4
Varity_R		0.065
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs2533731; hg19: chr7-153749963; COSMIC: COSV66710393; COSMIC: COSV66710393;