chr19-4090584-G-T

Variant names:

• chr19-4090584-G-T
• rs374728969
• NM_030662.4:c.*14C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_030662.4(MAP2K2):​c.*14C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000582 in 1,546,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374
• Publications: 0 publications found

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]

MAP2K2 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.*14C>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.*14C>A		3_prime_UTR_variant	Exon 9 of 9		NP_001427617.1
MAP2K2	NM_001440689.1	c.*14C>A		3_prime_UTR_variant	Exon 9 of 9		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.*14C>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

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

GnomAD2 exomes AF: 0.0000323 AC: 5 AN: 154774 AF XY: 0.0000366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000430 AC: 6 AN: 1393942 Hom.: 0 Cov.: 30 AF XY: 0.00000582 AC XY: 4 AN XY: 687874

African (AFR) AF: 0.00 AC: 0 AN: 31518

American (AMR) AF: 0.000168 AC: 6 AN: 35712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25140

East Asian (EAS) AF: 0.00 AC: 0 AN: 35742

South Asian (SAS) AF: 0.00 AC: 0 AN: 79116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4846

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075844

Other (OTH) AF: 0.00 AC: 0 AN: 57774

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.82
DANN	Benign	0.72
PhyloP100		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs374728969; hg19: chr19-4090582;