chr12-25209920-C-T

Variant names:

• chr12-25209920-C-T
• rs12313763
• NM_033360.4:c.*5-9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004985.5(KRAS):​c.451-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,596,712 control chromosomes in the GnomAD database, including 2,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1398 hom., cov: 33)
  • Exomes 𝑓: 0.011 (1282 hom.)
• Consequence: KRAS NM_004985.5 intron
• Scores: Splicing: ADA: 0.0009185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.592
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-25209920-C-T is Benign according to our data. Variant chr12-25209920-C-T is described in ClinVar as Benign. ClinVar VariationId is 40464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.256 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.*5-9G>A		intron	N/A	NP_203524.1
	KRAS	NM_004985.5	MANE Select	c.451-9G>A		intron	N/A	NP_004976.2
	KRAS	NM_001369786.1		c.*5-9G>A		intron	N/A	NP_001356715.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.*5-9G>A		intron	N/A	ENSP00000256078.5
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.451-9G>A		intron	N/A	ENSP00000308495.3
	KRAS	ENST00000685328.1		c.451-9G>A		intron	N/A	ENSP00000508921.1

Frequencies

GnomAD3 genomes AF: 0.0785 AC: 11928 AN: 151936 Hom.: 1392 Cov.: 33

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.0629

GnomAD2 exomes AF: 0.0244 AC: 5984 AN: 245520 AF XY: 0.0191

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000467

Gnomad NFE exome AF: 0.00442

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0112 AC: 16164 AN: 1444658 Hom.: 1282 Cov.: 28 AF XY: 0.0103 AC XY: 7391 AN XY: 719250

African (AFR) AF: 0.267 AC: 8680 AN: 32550

American (AMR) AF: 0.0229 AC: 996 AN: 43514

Ashkenazi Jewish (ASJ) AF: 0.0390 AC: 1007 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39352

South Asian (SAS) AF: 0.00182 AC: 153 AN: 84290

European-Finnish (FIN) AF: 0.000358 AC: 19 AN: 53018

Middle Eastern (MID) AF: 0.0544 AC: 310 AN: 5694

European-Non Finnish (NFE) AF: 0.00314 AC: 3455 AN: 1100710

Other (OTH) AF: 0.0259 AC: 1544 AN: 59698

GnomAD4 genome AF: 0.0786 AC: 11949 AN: 152054 Hom.: 1398 Cov.: 33 AF XY: 0.0758 AC XY: 5637 AN XY: 74340

African (AFR) AF: 0.260 AC: 10786 AN: 41432

American (AMR) AF: 0.0370 AC: 566 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00418 AC: 284 AN: 67966

Other (OTH) AF: 0.0622 AC: 131 AN: 2106

Alfa AF: 0.0510 Hom.: 391

Bravo AF: 0.0892

Asia WGS AF: 0.0180 AC: 61 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Noonan syndrome 3 (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.0
DANN	Benign	0.85
PhyloP100		-0.59
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.062
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: rs12313763; hg19: chr12-25362854; COSMIC: COSV55527560;