rs112542693

Variant names:

• chr15-66387263-G-C
• rs112542693
• NM_002755.4:c.-85G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-66387263-G-C
• chr15-66387263-G-T

Variant summary

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

The NM_002755.4(MAP2K1):​c.-85G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,243,106 control chromosomes in the GnomAD database, including 35,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3356 hom., cov: 33)
  • Exomes 𝑓: 0.24 (32150 hom.)
• Consequence: MAP2K1 NM_002755.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.38
• Publications: 16 publications found

Genes affected

MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

MAP2K1 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

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

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-66387263-G-C is Benign according to our data. Variant chr15-66387263-G-C is described in ClinVar as Benign. ClinVar VariationId is 1286889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002755.4. 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
	MAP2K1	NM_002755.4	MANE Select	c.-85G>C		5_prime_UTR	Exon 1 of 11	NP_002746.1	Q02750-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.-85G>C		5_prime_UTR	Exon 1 of 11	ENSP00000302486.5	Q02750-1
	MAP2K1	ENST00000685172.1		c.-85G>C		5_prime_UTR	Exon 1 of 10	ENSP00000509604.1	A0A8I5KYB4
	MAP2K1	ENST00000689951.1		c.-85G>C		5_prime_UTR	Exon 1 of 12	ENSP00000509308.1	A0A8I5KRX5

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28371 AN: 151944 Hom.: 3364 Cov.: 33

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.317

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.197

GnomAD4 exome AF: 0.236 AC: 257139 AN: 1091046 Hom.: 32150 Cov.: 14 AF XY: 0.239 AC XY: 131570 AN XY: 549408

African (AFR) AF: 0.0471 AC: 1182 AN: 25110

American (AMR) AF: 0.126 AC: 4304 AN: 34176

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 6931 AN: 22618

East Asian (EAS) AF: 0.107 AC: 3636 AN: 33934

South Asian (SAS) AF: 0.272 AC: 19586 AN: 71890

European-Finnish (FIN) AF: 0.252 AC: 12053 AN: 47828

Middle Eastern (MID) AF: 0.280 AC: 1110 AN: 3968

European-Non Finnish (NFE) AF: 0.245 AC: 197239 AN: 804216

Other (OTH) AF: 0.235 AC: 11098 AN: 47306

GnomAD4 genome AF: 0.186 AC: 28352 AN: 152060 Hom.: 3356 Cov.: 33 AF XY: 0.187 AC XY: 13922 AN XY: 74314

African (AFR) AF: 0.0523 AC: 2172 AN: 41546

American (AMR) AF: 0.174 AC: 2670 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1045 AN: 3466

East Asian (EAS) AF: 0.156 AC: 804 AN: 5138

South Asian (SAS) AF: 0.270 AC: 1301 AN: 4826

European-Finnish (FIN) AF: 0.260 AC: 2747 AN: 10560

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.248 AC: 16855 AN: 67908

Other (OTH) AF: 0.198 AC: 419 AN: 2112

Alfa AF: 0.225 Hom.: 543

Bravo AF: 0.170

Asia WGS AF: 0.219 AC: 760 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		1.4
PromoterAI		0.098	Neutral
Mutation Taster		=300/0	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: rs112542693; hg19: chr15-66679601; COSMIC: COSV107396853; COSMIC: COSV107396853;