rs746354996

chr15-66489734-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4 BS1_Supporting BS2

The NM_002755.4(MAP2K1):c.1039G>A(p.Ala347Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.47

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a domain Protein kinase (size 293) in uniprot entity MP2K1_HUMAN there are 48 pathogenic changes around while only 5 benign (91%) in NM_002755.4
• PP2: Missense variant where missense usually causes diseases, MAP2K1
• BP4: Computational evidence support a benign effect (MetaRNN=0.27007148).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000157 (23/1461576) while in subpopulation EAS AF= 0.0000252 (1/39700). AF 95% confidence interval is 0.0000118. There are 0 homozygotes in gnomad4_exome. There are 15 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4	c.1039G>A	p.Ala347Thr	missense_variant	10/11	ENST00000307102.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10	c.1039G>A	p.Ala347Thr	missense_variant	10/11	1	NM_002755.4	P1
	ENST00000565387.2	n.1092C>T		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251486 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461576 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 22, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Ala347Thr var iant in MAP2K1 has been reported prenatally in 1 fetus with unspecified abnormal ultrasound findings that may be suggestive of Noonan syndrome (Croonen 2013). T his variant was also identified by our laboratory in 1 individual with clinical features of Noonan syndrome and was inherited from an unaffected parent. This va riant has also been identified in 1/6614 of Finnish chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org). Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact to the protein. In summary, while the clinical significance of the p .Ala347Thr variant is uncertain, the fact that it was identified in an unaffecte d parent suggests that it is more likely to be benign. -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 13, 2021

This sequence change replaces alanine with threonine at codon 347 of the MAP2K1 protein (p.Ala347Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant has been reported in a fetus with features consistent with Noonan syndrome (PMID: 23321623). ClinVar contains an entry for this variant (Variation ID: 228846). This variant is present in population databases (rs746354996, ExAC 0.02%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0046	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	0.0036
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.29	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.20
Sift	Benign	0.50	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.10	B;.
Vest4		0.62
MutPred		0.31		Loss of catalytic residue at A347 (P = 0.1494);.;
MVP		0.75
MPC		0.34
ClinPred		0.19	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs746354996; hg19: chr15-66782072; COSMIC: COSV57233941; COSMIC: COSV57233941;