rs740576

Variant names:

• chr7-153889746-G-A
• rs740576
• ENST00000404039.5:c.51+2012G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000404039.5(DPP6):​c.51+2012G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,056 control chromosomes in the GnomAD database, including 3,673 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3673 hom., cov: 32)
• Consequence: DPP6 ENST00000404039.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 6 publications found

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]

DPP6 Gene-Disease associations (from GenCC):

• autosomal dominant primary microcephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal dominant 33

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ventricular fibrillation, paroxysmal familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPP6	NM_001364497.2	c.60+140738G>A		intron_variant	Intron 2 of 26		NP_001351426.1
DPP6	NM_001364498.2	c.60+140738G>A		intron_variant	Intron 2 of 26		NP_001351427.1
DPP6	NM_001364499.2	c.60+140738G>A		intron_variant	Intron 2 of 26		NP_001351428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPP6	ENST00000404039.5	c.51+2012G>A		intron_variant	Intron 1 of 25	1		ENSP00000385578.1
DPP6	ENST00000706130.1	c.60+140738G>A		intron_variant	Intron 2 of 26			ENSP00000516215.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33178 AN: 151938 Hom.: 3671 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.218 AC: 33194 AN: 152056 Hom.: 3673 Cov.: 32 AF XY: 0.223 AC XY: 16580 AN XY: 74308

African (AFR) AF: 0.216 AC: 8979 AN: 41474

American (AMR) AF: 0.211 AC: 3230 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 903 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1091 AN: 5166

South Asian (SAS) AF: 0.170 AC: 818 AN: 4822

European-Finnish (FIN) AF: 0.332 AC: 3503 AN: 10550

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13941 AN: 67964

Other (OTH) AF: 0.244 AC: 516 AN: 2112

Alfa AF: 0.211 Hom.: 7318

Bravo AF: 0.212

Asia WGS AF: 0.229 AC: 799 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.37
PhyloP100		0.28

Splicing

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

Other links and lift over

dbSNP: rs740576; hg19: chr7-153586831;