chr19-4101008-C-T

Variant names:

• chr19-4101008-C-T
• rs202086678
• NM_030662.4:c.705+11G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030662.4(MAP2K2):​c.705+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,552,966 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: MAP2K2 NM_030662.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0230

Genes affected

MAP2K2 (HGNC:6842): (mitogen-activated protein kinase kinase 2) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-4101008-C-T is Benign according to our data. Variant chr19-4101008-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000125 (19/151514) while in subpopulation SAS AF= 0.00167 (8/4794). AF 95% confidence interval is 0.00083. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.705+11G>A		intron_variant	Intron 6 of 10	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.705+11G>A		intron_variant	Intron 6 of 8		XP_006722862.1
MAP2K2	XM_047439100.1	c.135+11G>A		intron_variant	Intron 4 of 8		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.705+11G>A		intron_variant	Intron 6 of 10	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151398 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000358 AC: 58 AN: 161918 Hom.: 1 AF XY: 0.000410 AC XY: 35 AN XY: 85356

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000800

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000439

GnomAD4 exome AF: 0.000260 AC: 365 AN: 1401452 Hom.: 3 Cov.: 30 AF XY: 0.000294 AC XY: 203 AN XY: 691602

Gnomad4 AFR exome AF: 0.0000315

Gnomad4 AMR exome AF: 0.0000835

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.000361

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151514 Hom.: 0 Cov.: 31 AF XY: 0.000176 AC XY: 13 AN XY: 74014

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.0000857 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 30, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MAP2K2 c.705+11G>A 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. 5/5 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 0.00036 in 161918 control chromosomes, predominantly at a frequency of 0.002 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 800 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.705+11G>A 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, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Oct 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.705+11G>A in intron 6 of MAP2K2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. I t has been identified in 0.2% (19/7954) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202086678) . -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Benign:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

Other links and lift over

dbSNP: rs202086678; hg19: chr19-4101006;