chr7-154053046-G-A

Variant names:

• chr7-154053046-G-A
• rs569787719
• NM_130797.4:c.226G>A

Variant summary

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

The NM_130797.4(DPP6):​c.226G>A​(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0226 in 1,058,538 control chromosomes in the GnomAD database, including 312 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (26 hom., cov: 31)
  • Exomes 𝑓: 0.024 (286 hom.)
• Consequence: DPP6 NM_130797.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.63
• Publications: 5 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
• ventricular fibrillation, paroxysmal familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability, autosomal dominant 33

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000203335 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023885071).
• BP6: Variant 7-154053046-G-A is Benign according to our data. Variant chr7-154053046-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 377138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0161 (2407/149904) while in subpopulation SAS AF = 0.0288 (137/4760). AF 95% confidence interval is 0.0249. There are 26 homozygotes in GnomAd4. There are 1253 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2407 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130797.4. 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
	DPP6	NM_130797.4	MANE Select	c.226G>A	p.Asp76Asn	missense	Exon 1 of 26	NP_570629.2	P42658-1
	DPP6	NM_001290253.2		c.226G>A	p.Asp76Asn	missense	Exon 1 of 6	NP_001277182.1	Q8IYG9
	DPP6	NM_001364497.2		c.60+304038G>A		intron	N/A	NP_001351426.1	A0A994J7K0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPP6	ENST00000377770.8	TSL:1 MANE Select	c.226G>A	p.Asp76Asn	missense	Exon 1 of 26	ENSP00000367001.3	P42658-1
	DPP6	ENST00000406326.5	TSL:1	c.226G>A	p.Asp76Asn	missense	Exon 1 of 6	ENSP00000384393.1	Q8IYG9
	DPP6	ENST00000404039.5	TSL:1	c.51+165312G>A		intron	N/A	ENSP00000385578.1	E9PF59

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2406 AN: 149792 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.00402

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0285

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0155

GnomAD2 exomes AF: 0.0286 AC: 63 AN: 2200 AF XY: 0.0297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0237 AC: 21490 AN: 908634 Hom.: 286 Cov.: 37 AF XY: 0.0236 AC XY: 10017 AN XY: 424422

African (AFR) AF: 0.00231 AC: 41 AN: 17744

American (AMR) AF: 0.00804 AC: 24 AN: 2984

Ashkenazi Jewish (ASJ) AF: 0.00953 AC: 72 AN: 7558

East Asian (EAS) AF: 0.0000901 AC: 1 AN: 11096

South Asian (SAS) AF: 0.0312 AC: 565 AN: 18124

European-Finnish (FIN) AF: 0.0261 AC: 223 AN: 8542

Middle Eastern (MID) AF: 0.0153 AC: 33 AN: 2154

European-Non Finnish (NFE) AF: 0.0245 AC: 19781 AN: 808678

Other (OTH) AF: 0.0236 AC: 750 AN: 31754

GnomAD4 genome AF: 0.0161 AC: 2407 AN: 149904 Hom.: 26 Cov.: 31 AF XY: 0.0171 AC XY: 1253 AN XY: 73148

African (AFR) AF: 0.00401 AC: 165 AN: 41124

American (AMR) AF: 0.0134 AC: 202 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5002

South Asian (SAS) AF: 0.0288 AC: 137 AN: 4760

European-Finnish (FIN) AF: 0.0367 AC: 363 AN: 9882

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1449 AN: 67334

Other (OTH) AF: 0.0153 AC: 32 AN: 2090

Alfa AF: 0.00577 Hom.: 0

Bravo AF: 0.0131

ExAC AF: 0.00978 AC: 134

Asia WGS AF: 0.00956 AC: 33 AN: 3466

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.58	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.92	T
PhyloP100		3.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.13
MPC		0.42
ClinPred		0.072	T
GERP RS		2.3
Varity_R		0.11
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs569787719; hg19: chr7-153750131; COSMIC: COSV66710423; COSMIC: COSV66710423;