rs113623140

chr12-25245295-G-Achr12-25245295-G-Cchr12-25245295-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004985.5(KRAS):c.90C>T(p.Asp30=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,610,502 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 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: KRAS NM_004985.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 1.16

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-25245295-G-A is Benign according to our data. Variant chr12-25245295-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138061.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-25245295-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000119 (173/1458330) while in subpopulation MID AF= 0.000694 (4/5762). AF 95% confidence interval is 0.000397. There are 1 homozygotes in gnomad4_exome. There are 100 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_033360.4	c.90C>T	p.Asp30=	synonymous_variant	2/6	ENST00000256078.10
KRAS	NM_004985.5	c.90C>T	p.Asp30=	synonymous_variant	2/5	ENST00000311936.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.90C>T	p.Asp30=	synonymous_variant	2/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.90C>T	p.Asp30=	synonymous_variant	2/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 50 AN: 246426 Hom.: 1 AF XY: 0.000203 AC XY: 27 AN XY: 133066

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.000438

Gnomad SAS exome AF: 0.000100

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000993

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000119 AC: 173 AN: 1458330 Hom.: 1 Cov.: 31 AF XY: 0.000138 AC XY: 100 AN XY: 725148

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.000580

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.0000685

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74404

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000244 Hom.: 0

Bravo AF: 0.000155

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	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

Likely benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	The filtering allele frequency of the c.90C>T (p.Asp30=) variant in the KRAS gene is 0.0292% (5/6746) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

Prostate cancer, hereditary, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca

Jul 29, 2022

- -

Malignant tumor of urinary bladder;C0023467:Acute myeloid leukemia;C0024623:Gastric cancer;C0235974:Carcinoma of pancreas;C0242379:Lung cancer;C0346153:Familial cancer of breast;C0917804:Cerebral arteriovenous malformation;C1838329:Toriello-Lacassie-Droste syndrome;C1860991:Noonan syndrome 3;C2674723:Autoimmune lymphoproliferative syndrome type 4;C3809005:Cardiofaciocutaneous syndrome 2;C4552097:Linear nevus sebaceous syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	12
Dann	Benign	0.59

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

Other links and lift over

dbSNP: rs113623140; hg19: chr12-25398229;