NM_004985.5:c.519T>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BP4BP7

This summary comes from the ClinGen Evidence Repository: The c.519T>C variant in the KRAS gene is a synonymous (silent) variant (p.Asp173=) at a nucleotide that is not conserved as shown by UCSC browser, and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v2.1.1 is 0.2201 (28382/128282 alleles with 3073 homozygotes) in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP7 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA135582/MONDO:0021060/044

Frequency

Genomes: 𝑓 0.20 ( 2983 hom., cov: 33)

Exomes 𝑓: 0.21 ( 31762 hom. )

Consequence

KRAS
NM_004985.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:15

Conservation

PhyloP100: 0.886

Variant links:

Genes affected

KRAS (HGNC:6407): (KRAS proto-oncogene, GTPase) This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]

KRAS links:

ETFRF1 (HGNC:27052): (electron transfer flavoprotein regulatory factor 1) Involved in respiratory electron transport chain. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ETFRF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5 link	c.519T>C	p.Asp173Asp	synonymous_variant	Exon 5 of 5	ENST00000311936.8	NP_004976.2	P01116-2A0A024RAV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8 link	c.519T>C	p.Asp173Asp	synonymous_variant	Exon 5 of 5	1	NM_004985.5	ENSP00000308495.3		P01116-2

Frequencies

GnomAD3 genomes

AF:

0.195

AC:

29671

AN:

151992

Hom.:

2977

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.396

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.0981

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.220

Gnomad OTH

AF:

0.204

GnomAD3 exomes

AF:

0.191

AC:

47675

AN:

249898

Hom.:

4761

AF XY:

0.194

AC XY:

26205

AN XY:

135124

show subpopulations

Gnomad AFR exome

AF:

0.177

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.163

Gnomad EAS exome

AF:

0.0958

Gnomad SAS exome

AF:

0.191

Gnomad FIN exome

AF:

0.156

Gnomad NFE exome

AF:

0.222

Gnomad OTH exome

AF:

0.209

GnomAD4 exome

AF:

0.207

AC:

301862

AN:

1457408

Hom.:

31762

Cov.:

AF XY:

0.207

AC XY:

149768

AN XY:

725240

show subpopulations

Gnomad4 AFR exome

AF:

0.177

Gnomad4 AMR exome

AF:

0.175

Gnomad4 ASJ exome

AF:

0.162

Gnomad4 EAS exome

AF:

0.116

Gnomad4 SAS exome

AF:

0.193

Gnomad4 FIN exome

AF:

0.162

Gnomad4 NFE exome

AF:

0.217

Gnomad4 OTH exome

AF:

0.201

GnomAD4 genome

AF:

0.195

AC:

29692

AN:

152110

Hom.:

2983

Cov.:

AF XY:

0.190

AC XY:

14159

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.175

Gnomad4 AMR

AF:

0.196

Gnomad4 ASJ

AF:

0.170

Gnomad4 EAS

AF:

0.0981

Gnomad4 SAS

AF:

0.193

Gnomad4 FIN

AF:

0.150

Gnomad4 NFE

AF:

0.220

Gnomad4 OTH

AF:

0.206

Alfa

AF:

0.213

Hom.:

3561

Bravo

AF:

0.196

Asia WGS

AF:

0.183

AC:

634

AN:

3466

EpiCase

AF:

0.216

EpiControl

AF:

0.222

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:8

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 08, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 19, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 07, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

RASopathy

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.519T>C variant in the KRAS gene is a synonymous (silent) variant (p.Asp173=) at a nucleotide that is not conserved as shown by UCSC browser, and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v2.1.1 is 0.2201 (28382/128282 alleles with 3073 homozygotes) in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP7 (Specification Version 2.3, 12/3/2024) -

Noonan syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 19, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

7.9

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over