1-162780159-G-T

Position:

• chr1-162780159-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006182.4(DDR2):​c.2481G>T​(p.Leu827Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,902 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00065 (13 hom.)
• Consequence: DDR2 NM_006182.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.25

Genes affected

DDR2 (HGNC:2731): (discoidin domain receptor tyrosine kinase 2) This gene encodes a member of the discoidin domain receptor subclass of the receptor tyrosine kinase (RTKs) protein family. RTKs play a key role in the communication of cells with their microenvironment. The encoded protein is a collagen-induced receptor that activates signal transduction pathways involved in cell adhesion, proliferation, and extracellular matrix remodeling. This protein is expressed in numerous cell types and may alos be involved in wound repair and regulate tumor growth and invasiveness. Mutations in this gene are the cause of short limb-hand type spondylometaepiphyseal dysplasia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-162780159-G-T is Benign according to our data. Variant chr1-162780159-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259933.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}.
• BP7: Synonymous conserved (PhyloP=1.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00658 (1001/152124) while in subpopulation AFR AF= 0.0224 (928/41518). AF 95% confidence interval is 0.0212. There are 14 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1001 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDR2	NM_006182.4	c.2481G>T	p.Leu827Leu	synonymous_variant	18/18	ENST00000367921.8	NP_006173.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDR2	ENST00000367921.8	c.2481G>T	p.Leu827Leu	synonymous_variant	18/18	1	NM_006182.4	ENSP00000356898.3
DDR2	ENST00000367922.7	c.2481G>T	p.Leu827Leu	synonymous_variant	19/19	1		ENSP00000356899.2
DDR2	ENST00000446985.6	c.2481G>T	p.Leu827Leu	synonymous_variant	18/18	3		ENSP00000400309.2

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1002 AN: 152006 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00163 AC: 409 AN: 251276 Hom.: 8 AF XY: 0.00113 AC XY: 154 AN XY: 135812

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.000653 AC: 954 AN: 1461778 Hom.: 13 Cov.: 34 AF XY: 0.000529 AC XY: 385 AN XY: 727198

Gnomad4 AFR exome AF: 0.0244

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00658 AC: 1001 AN: 152124 Hom.: 14 Cov.: 31 AF XY: 0.00596 AC XY: 443 AN XY: 74362

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.00328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00369 Hom.: 2

Bravo AF: 0.00748

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.9
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35077871; hg19: chr1-162749949;