chr12-25246187-A-C

Variant names:

• chr12-25246187-A-C
• rs11047919
• NM_033360.4:c.-11-792T>G

Variant summary

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

The NM_033360.4(KRAS):​c.-11-792T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 148,304 control chromosomes in the GnomAD database, including 17,882 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 0.46 (17882 hom., cov: 27)
• Consequence: KRAS NM_033360.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 14 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.-11-792T>G		intron	N/A	NP_203524.1
	KRAS	NM_004985.5	MANE Select	c.-11-792T>G		intron	N/A	NP_004976.2
	KRAS	NM_001369786.1		c.-11-792T>G		intron	N/A	NP_001356715.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.-11-792T>G		intron	N/A	ENSP00000256078.5
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.-11-792T>G		intron	N/A	ENSP00000308495.3
	KRAS	ENST00000556131.2	TSL:1	c.-11-792T>G		intron	N/A	ENSP00000451856.1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 68507 AN: 148200 Hom.: 17879 Cov.: 27

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.480

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

GnomAD4 genome AF: 0.462 AC: 68518 AN: 148304 Hom.: 17882 Cov.: 27 AF XY: 0.464 AC XY: 33323 AN XY: 71832

African (AFR) AF: 0.211 AC: 8515 AN: 40430

American (AMR) AF: 0.496 AC: 7284 AN: 14696

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1971 AN: 3460

East Asian (EAS) AF: 0.799 AC: 3998 AN: 5006

South Asian (SAS) AF: 0.585 AC: 2778 AN: 4746

European-Finnish (FIN) AF: 0.533 AC: 4876 AN: 9144

Middle Eastern (MID) AF: 0.500 AC: 143 AN: 286

European-Non Finnish (NFE) AF: 0.556 AC: 37556 AN: 67584

Other (OTH) AF: 0.481 AC: 987 AN: 2050

Alfa AF: 0.536 Hom.: 12285

Bravo AF: 0.452

Asia WGS AF: 0.655 AC: 2278 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.1
DANN	Benign	0.49
PhyloP100		1.1
Mutation Taster		=100/0	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: rs11047919; hg19: chr12-25399121;