rs61759617

Positions:

• chr12-25250861-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004985.5(KRAS):​c.-122C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 246,296 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: KRAS NM_004985.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.28

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-25250861-G-A is Benign according to our data. Variant chr12-25250861-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 177710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00132 (200/151514) while in subpopulation AFR AF= 0.00469 (194/41342). AF 95% confidence interval is 0.00415. There are 1 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 200 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5	c.-122C>T		5_prime_UTR_variant	1/5	ENST00000311936.8	NP_004976.2
KRAS	NM_033360.4	c.-122C>T		5_prime_UTR_variant	1/6	ENST00000256078.10	NP_203524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000256078.10	c.-122C>T		5_prime_UTR_variant	1/6	1	NM_033360.4	ENSP00000256078	A1
KRAS	ENST00000311936.8	c.-122C>T		5_prime_UTR_variant	1/5	1	NM_004985.5	ENSP00000308495	P4

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 151402 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000482

GnomAD4 exome AF: 0.000200 AC: 19 AN: 94782 Hom.: 0 Cov.: 0 AF XY: 0.000178 AC XY: 9 AN XY: 50552

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000389

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000322

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00132 AC: 200 AN: 151514 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 96 AN XY: 74034

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.00146

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 20, 2011

This variant has been reported in dbSNP in 1/20 (5%) Black individuals (rs617596 17). In addition, this variant occurs in the 5' UTR of the gene and even though mutations in 5' UTRs of genes have been shown to affect gene regulation, no pat hogenic mutations in the 5' UTR of KRAS have been reported to date. Therefore, t his variant is not expected to have clinical significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61759617; hg19: chr12-25403795;