ENST00000425818.2:n.64C>T

Variant names:

• chr15-66386900-C-T
• rs73469977
• ENST00000425818.2:n.64C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000425818.2(MAP2K1):​n.64C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 235,324 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: MAP2K1 ENST00000425818.2 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.202
• Publications: 1 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]

TIPIN (HGNC:30750): (TIMELESS interacting protein) The protein encoded by this gene is part of the replisome complex, a group of proteins that support DNA replication. It binds TIM, which is involved in circadian rhythm regulation, and aids in protecting cells against DNA damage and stress. Two pseudogenes and two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 15-66386900-C-T is Benign according to our data. Variant chr15-66386900-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 316831.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.005 (761/152352) while in subpopulation AFR AF = 0.0176 (734/41592). AF 95% confidence interval is 0.0166. There are 10 homozygotes in GnomAd4. There are 367 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 761 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.-448C>T		upstream_gene_variant		ENST00000307102.10	NP_002746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.-448C>T		upstream_gene_variant		1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 758 AN: 152234 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

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: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.000880 AC: 73 AN: 82972 Hom.: 0 Cov.: 0 AF XY: 0.000751 AC XY: 29 AN XY: 38614

African (AFR) AF: 0.0147 AC: 56 AN: 3818

American (AMR) AF: 0.000404 AC: 1 AN: 2474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5122

East Asian (EAS) AF: 0.00 AC: 0 AN: 11322

South Asian (SAS) AF: 0.00 AC: 0 AN: 920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 482

European-Non Finnish (NFE) AF: 0.0000774 AC: 4 AN: 51694

Other (OTH) AF: 0.00176 AC: 12 AN: 6808

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152352 Hom.: 10 Cov.: 33 AF XY: 0.00493 AC XY: 367 AN XY: 74508

African (AFR) AF: 0.0176 AC: 734 AN: 41592

American (AMR) AF: 0.000980 AC: 15 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.0000698 Hom.: 0

Bravo AF: 0.00544

Asia WGS AF: 0.00115 AC: 5 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 31, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Uncertain	0.99
PhyloP100		-0.20
PromoterAI		-0.12	Neutral
Mutation Taster		=285/15	polymorphism

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: rs73469977; hg19: chr15-66679238;