rs12313763

chr12-25209920-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004985.5(KRAS):c.451-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,596,712 control chromosomes in the GnomAD database, including 2,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1398 hom., cov: 33)
  • Exomes 𝑓: 0.011 (1282 hom.)
• Consequence: KRAS NM_004985.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0009185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.592

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-25209920-C-T is Benign according to our data. Variant chr12-25209920-C-T is described in ClinVar as [Benign]. Clinvar id is 40464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25209920-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.451-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000311936.8
KRAS	NM_033360.4	c.*5-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000256078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.*5-9G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.451-9G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.0785 AC: 11928 AN: 151936 Hom.: 1392 Cov.: 33

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.0629

GnomAD3 exomes AF: 0.0244 AC: 5984 AN: 245520 Hom.: 580 AF XY: 0.0191 AC XY: 2544 AN XY: 132910

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.000467

Gnomad NFE exome AF: 0.00442

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0112 AC: 16164 AN: 1444658 Hom.: 1282 Cov.: 28 AF XY: 0.0103 AC XY: 7391 AN XY: 719250

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.000358

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0786 AC: 11949 AN: 152054 Hom.: 1398 Cov.: 33 AF XY: 0.0758 AC XY: 5637 AN XY: 74340

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.0370

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.0622

Alfa AF: 0.0488 Hom.: 366

Bravo AF: 0.0892

Asia WGS AF: 0.0180 AC: 61 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 06, 2007	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

Noonan syndrome 3 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

RASopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	6.0
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.062
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

Other links and lift over

dbSNP: rs12313763; hg19: chr12-25362854; COSMIC: COSV55527560; COSMIC: COSV55527560;