chr15-66436912-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002755.4(MAP2K1):​c.438+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,613,606 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 37 hom., cov: 32)
Exomes 𝑓: 0.025 ( 628 hom. )

Consequence

MAP2K1
NM_002755.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.191
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 15-66436912-C-T is Benign according to our data. Variant chr15-66436912-C-T is described in ClinVar as [Benign]. Clinvar id is 40749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66436912-C-T is described in Lovd as [Benign].
BA1
GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0628 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAP2K1NM_002755.4 linkuse as main transcriptc.438+20C>T intron_variant ENST00000307102.10
MAP2K1NM_001411065.1 linkuse as main transcriptc.372+20C>T intron_variant
MAP2K1XM_011521783.4 linkuse as main transcriptc.372+20C>T intron_variant
MAP2K1XM_017022411.3 linkuse as main transcriptc.438+20C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAP2K1ENST00000307102.10 linkuse as main transcriptc.438+20C>T intron_variant 1 NM_002755.4 P1Q02750-1

Frequencies

GnomAD3 genomes
AF:
0.0174
AC:
2641
AN:
152174
Hom.:
37
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00427
Gnomad AMI
AF:
0.0132
Gnomad AMR
AF:
0.0132
Gnomad ASJ
AF:
0.0115
Gnomad EAS
AF:
0.0162
Gnomad SAS
AF:
0.0540
Gnomad FIN
AF:
0.0129
Gnomad MID
AF:
0.0348
Gnomad NFE
AF:
0.0246
Gnomad OTH
AF:
0.0211
GnomAD3 exomes
AF:
0.0251
AC:
6300
AN:
251342
Hom.:
113
AF XY:
0.0278
AC XY:
3778
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00344
Gnomad AMR exome
AF:
0.0116
Gnomad ASJ exome
AF:
0.0125
Gnomad EAS exome
AF:
0.0119
Gnomad SAS exome
AF:
0.0632
Gnomad FIN exome
AF:
0.0151
Gnomad NFE exome
AF:
0.0271
Gnomad OTH exome
AF:
0.0259
GnomAD4 exome
AF:
0.0247
AC:
36107
AN:
1461314
Hom.:
628
Cov.:
32
AF XY:
0.0260
AC XY:
18903
AN XY:
726974
show subpopulations
Gnomad4 AFR exome
AF:
0.00341
Gnomad4 AMR exome
AF:
0.0111
Gnomad4 ASJ exome
AF:
0.0140
Gnomad4 EAS exome
AF:
0.0209
Gnomad4 SAS exome
AF:
0.0643
Gnomad4 FIN exome
AF:
0.0149
Gnomad4 NFE exome
AF:
0.0237
Gnomad4 OTH exome
AF:
0.0232
GnomAD4 genome
AF:
0.0174
AC:
2646
AN:
152292
Hom.:
37
Cov.:
32
AF XY:
0.0173
AC XY:
1290
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00438
Gnomad4 AMR
AF:
0.0132
Gnomad4 ASJ
AF:
0.0115
Gnomad4 EAS
AF:
0.0158
Gnomad4 SAS
AF:
0.0551
Gnomad4 FIN
AF:
0.0129
Gnomad4 NFE
AF:
0.0246
Gnomad4 OTH
AF:
0.0208
Alfa
AF:
0.0201
Hom.:
11
Bravo
AF:
0.0163
Asia WGS
AF:
0.0400
AC:
140
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJan 15, 2015- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 01, 2019Variant summary: MAP2K1 c.438+20C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.025 in 251342 control chromosomes in the gnomAD database, including 113 homozygotes. The observed variant frequency is approximately 10026 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.438+20C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 03, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Cardiofaciocutaneous syndrome 3 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
RASopathy Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
2.1
DANN
Benign
0.41

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs16949939; hg19: chr15-66729250; COSMIC: COSV61068907; API