15-66481747-C-T

Variant names:

• chr15-66481747-C-T
• rs375614631
• NM_002755.4:c.569-8C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_002755.4(MAP2K1):​c.569-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAP2K1 NM_002755.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002891
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.336
• Publications: 0 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: Orphanet, ClinGen
• cardiofaciocutaneous syndrome 3

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-66481747-C-T is Benign according to our data. Variant chr15-66481747-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 517177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.569-8C>T		splice_region_variant, intron_variant	Intron 5 of 10	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.425-8C>T		splice_region_variant, intron_variant	Intron 4 of 9		NP_001397994.1
MAP2K1	XM_011521783.4	c.503-8C>T		splice_region_variant, intron_variant	Intron 5 of 10		XP_011520085.1
MAP2K1	XM_017022411.3	c.491-8C>T		splice_region_variant, intron_variant	Intron 4 of 9		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.569-8C>T		splice_region_variant, intron_variant	Intron 5 of 10	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459628 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726158

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4438

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111596

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.569-8C>T in intron 5 of MAP2K1: This variant is not expected to have clinical significance because a C>T change at this position does not diverge from the spl ice consensus sequence and is therefore unlikely to impact splicing. -

RASopathy Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.81
CADD	Benign	6.1
DANN	Benign	0.56
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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: rs375614631; hg19: chr15-66774085;