rs4623993

Variant names:

• chr12-25232494-C-T
• rs4623993
• NM_033360.4:c.112-5082G>A

Variant summary

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

The NM_004985.5(KRAS):​c.112-5082G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 151,914 control chromosomes in the GnomAD database, including 2,852 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 0.19 (2852 hom., cov: 32)
• Consequence: KRAS NM_004985.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.898
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Noonan syndrome

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

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_033360.4	MANE Plus Clinical	c.112-5082G>A		intron	N/A	NP_203524.1	P01116-1
	KRAS	NM_004985.5	MANE Select	c.112-5082G>A		intron	N/A	NP_004976.2
	KRAS	NM_001369786.1		c.112-5082G>A		intron	N/A	NP_001356715.1	P01116-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.112-5082G>A		intron	N/A	ENSP00000256078.5	P01116-1
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.112-5082G>A		intron	N/A	ENSP00000308495.3	P01116-2
	KRAS	ENST00000685328.1		c.112-5082G>A		intron	N/A	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28201 AN: 151798 Hom.: 2838 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.0935

Gnomad EAS AF: 0.0973

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.157

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

GnomAD4 genome AF: 0.186 AC: 28244 AN: 151914 Hom.: 2852 Cov.: 32 AF XY: 0.190 AC XY: 14075 AN XY: 74244

African (AFR) AF: 0.269 AC: 11133 AN: 41420

American (AMR) AF: 0.185 AC: 2820 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0935 AC: 324 AN: 3466

East Asian (EAS) AF: 0.0976 AC: 504 AN: 5166

South Asian (SAS) AF: 0.130 AC: 627 AN: 4816

European-Finnish (FIN) AF: 0.244 AC: 2570 AN: 10532

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9827 AN: 67952

Other (OTH) AF: 0.155 AC: 326 AN: 2098

Alfa AF: 0.172 Hom.: 406

Bravo AF: 0.186

Asia WGS AF: 0.0950 AC: 330 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.86
DANN	Benign	0.20
PhyloP100		-0.90
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: rs4623993; hg19: chr12-25385428;