chr12-25209828-TTTC-T

Position:

chr12-25209828-TTTC-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PM4_SupportingBP6_Very_StrongBS1BS2

The NM_004985.5(KRAS):c.531_533delGAA(p.Lys178del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,758 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

KRAS
NM_004985.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: 7.63

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM1

In a chain GTPase KRas, N-terminally processed (size 184) in uniprot entity RASK_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_004985.5

PM4

Nonframeshift variant in NON repetitive region in NM_004985.5. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 12-25209828-TTTC-T is Benign according to our data. Variant chr12-25209828-TTTC-T is described in ClinVar as [Benign]. Clinvar id is 45129.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-25209828-TTTC-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000683 (104/152298) while in subpopulation NFE AF= 0.00126 (86/67992). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5 link	c.531_533delGAA	p.Lys178del	disruptive_inframe_deletion	5/5	ENST00000311936.8	NP_004976.2	P01116-2A0A024RAV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8 link	c.531_533delGAA	p.Lys178del	disruptive_inframe_deletion	5/5	1	NM_004985.5	ENSP00000308495.3		P01116-2

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000573

AC:

143

AN:

249744

Hom.:

AF XY:

0.000578

AC XY:

AN XY:

135056

show subpopulations

Gnomad AFR exome

AF:

0.000497

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00112

AC:

1628

AN:

1458460

Hom.:

AF XY:

0.00109

AC XY:

788

AN XY:

725740

show subpopulations

Gnomad4 AFR exome

AF:

0.000450

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00140

Gnomad4 OTH exome

AF:

0.000631

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152298

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000665

EpiCase

AF:

0.000929

EpiControl

AF:

0.000949

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	KRAS: PM4:Supporting, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 21, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

RASopathy

Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	The c.531_533delGAA variant in the KRAS gene is an in-frame deletion of the amino acid lysine (Lys) at position 180 (p.Lys180del). The gnomAD v.4.1.0 filtering allele frequency of this variant is 0.1339% for European (non-Finnish) chromosomes (1637/1177578 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR ID's: 21766, 26957; ClinVar SCV000061947, SCV000207865). 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, BP5 (Specification Version 2.1, 09/17/2024) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2017	p.Lys180del in exon 6 of KRAS: This variant is not expected to have clinical sig nificance because it has been identified in 0.1% (123/125888) European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517043). In addition, it was identified in one individual with featu res of Noonan syndrome who also carried a pathogenic variant in KRAS, which was sufficient to explain their phenotype, and in two parents, one whose disease sta tus was unknown and the other who was unaffected (LMM unpublished data). This va riant causes an in-frame deletion of the amino acid lysine (Lys) at position 180 . This amino acid is in a stretch of six lysine (Lys) residues. -

KRAS-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

This alteration is classified as likely 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. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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