12-25223395-A-G

Variant names:

• chr12-25223395-A-G
• rs11047901
• NM_004985.5:c.450+2219T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004985.5(KRAS):​c.450+2219T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 151,970 control chromosomes in the GnomAD database, including 19,420 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (19420 hom., cov: 32)
• Consequence: KRAS NM_004985.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19
• Publications: 11 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]

KRAS Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• linear nevus sebaceous syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.450+2219T>C		intron_variant	Intron 4 of 4	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.450+2219T>C		intron_variant	Intron 4 of 4	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74879 AN: 151852 Hom.: 19408 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.507

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.493 AC: 74921 AN: 151970 Hom.: 19420 Cov.: 32 AF XY: 0.499 AC XY: 37057 AN XY: 74276

African (AFR) AF: 0.328 AC: 13595 AN: 41464

American (AMR) AF: 0.502 AC: 7666 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2167 AN: 3470

East Asian (EAS) AF: 0.800 AC: 4150 AN: 5188

South Asian (SAS) AF: 0.668 AC: 3217 AN: 4814

European-Finnish (FIN) AF: 0.544 AC: 5722 AN: 10520

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36813 AN: 67922

Other (OTH) AF: 0.508 AC: 1074 AN: 2114

Alfa AF: 0.535 Hom.: 10062

Bravo AF: 0.482

Asia WGS AF: 0.690 AC: 2389 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.9
DANN	Benign	0.75
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11047901; hg19: chr12-25376329;