rs1137282

Variant names:

• chr12-25209843-A-G
• rs1137282
• NM_004985.5:c.519T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-25209843-A-G
• chr12-25209843-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BA1 BP4

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
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: 0.886
• Publications: 62 publications found

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]

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]

ACMG classification

Specifications for KRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004985.5. 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
	KRAS	NM_004985.5	MANE Select	c.519T>C	p.Asp173Asp	synonymous	Exon 5 of 5	NP_004976.2
	KRAS	NM_033360.4	MANE Plus Clinical	c.*73T>C		3_prime_UTR	Exon 6 of 6	NP_203524.1	P01116-1
	KRAS	NM_001369787.1		c.519T>C	p.Asp173Asp	synonymous	Exon 5 of 5	NP_001356716.1	P01116-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.519T>C	p.Asp173Asp	synonymous	Exon 5 of 5	ENSP00000308495.3	P01116-2
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.*73T>C		3_prime_UTR	Exon 6 of 6	ENSP00000256078.5	P01116-1
	KRAS	ENST00000685328.1		c.519T>C	p.Asp173Asp	synonymous	Exon 5 of 5	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29671 AN: 151992 Hom.: 2977 Cov.: 33

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

GnomAD2 exomes AF: 0.191 AC: 47675 AN: 249898 AF XY: 0.194

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 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.: 31 AF XY: 0.207 AC XY: 149768 AN XY: 725240

African (AFR) AF: 0.177 AC: 5897 AN: 33334

American (AMR) AF: 0.175 AC: 7787 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 4222 AN: 26068

East Asian (EAS) AF: 0.116 AC: 4580 AN: 39500

South Asian (SAS) AF: 0.193 AC: 16579 AN: 85978

European-Finnish (FIN) AF: 0.162 AC: 8620 AN: 53286

Middle Eastern (MID) AF: 0.237 AC: 1358 AN: 5740

European-Non Finnish (NFE) AF: 0.217 AC: 240697 AN: 1108670

Other (OTH) AF: 0.201 AC: 12122 AN: 60232

GnomAD4 genome AF: 0.195 AC: 29692 AN: 152110 Hom.: 2983 Cov.: 33 AF XY: 0.190 AC XY: 14159 AN XY: 74350

African (AFR) AF: 0.175 AC: 7279 AN: 41526

American (AMR) AF: 0.196 AC: 3001 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 589 AN: 3470

East Asian (EAS) AF: 0.0981 AC: 509 AN: 5186

South Asian (SAS) AF: 0.193 AC: 930 AN: 4822

European-Finnish (FIN) AF: 0.150 AC: 1581 AN: 10564

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14938 AN: 67942

Other (OTH) AF: 0.206 AC: 434 AN: 2106

Alfa AF: 0.212 Hom.: 5378

Bravo AF: 0.196

Asia WGS AF: 0.183 AC: 634 AN: 3466

EpiCase AF: 0.216

EpiControl AF: 0.222

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	7.9
DANN	Benign	0.79
PhyloP100		0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1137282; hg19: chr12-25362777; COSMIC: COSV55562336; COSMIC: COSV55562336;