NM_002755.4:c.1023-8C>T

Variant names:

• chr15-66489710-C-T
• rs41306345
• NM_002755.4:c.1023-8C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1023-8C>T variant in the MAP2K1 gene is 10.315% (1128/10406) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134590/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.093 (645 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5373 hom.)
• Consequence: MAP2K1 NM_002755.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003322
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.321
• Publications: 15 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]

ENSG00000261351 (HGNC:):

SNAPC5 (HGNC:15484): (small nuclear RNA activating complex polypeptide 5) This gene encodes a subunit of the small nuclear RNA (snRNA)-activating protein complex that plays a role in the transcription of snRNA genes. This complex binds to the promoters of snRNA genes transcribed by either RNA polymerase II or III and recruits other regulatory factors to activate snRNA gene transcription. The encoded protein may play a role in stabilizing this complex. A pseudogene of this gene has been identified on chromosome 6. [provided by RefSeq, Jul 2016]

ACMG classification

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

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002755.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	NM_002755.4	MANE Select	c.1023-8C>T		splice_region intron	N/A	NP_002746.1
	MAP2K1	NM_001411065.1		c.879-8C>T		splice_region intron	N/A	NP_001397994.1
	SNAPC5	NM_006049.4		c.*1029G>A		downstream_gene	N/A	NP_006040.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.1023-8C>T		splice_region intron	N/A	ENSP00000302486.5
	ENSG00000261351	ENST00000565387.2	TSL:1	n.1116G>A		non_coding_transcript_exon	Exon 2 of 2
	MAP2K1	ENST00000685172.1		c.1022+434C>T		intron	N/A	ENSP00000509604.1

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14067 AN: 152068 Hom.: 643 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0719

Gnomad ASJ AF: 0.0953

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.0817

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.0856

GnomAD2 exomes AF: 0.0840 AC: 21132 AN: 251480 AF XY: 0.0845

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0568

Gnomad ASJ exome AF: 0.0860

Gnomad EAS exome AF: 0.0480

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.0869

Gnomad OTH exome AF: 0.0894

GnomAD4 exome AF: 0.0842 AC: 122769 AN: 1458072 Hom.: 5373 Cov.: 30 AF XY: 0.0842 AC XY: 61084 AN XY: 725642

African (AFR) AF: 0.111 AC: 3719 AN: 33388

American (AMR) AF: 0.0585 AC: 2618 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 2338 AN: 26088

East Asian (EAS) AF: 0.0430 AC: 1707 AN: 39686

South Asian (SAS) AF: 0.0843 AC: 7264 AN: 86172

European-Finnish (FIN) AF: 0.115 AC: 6140 AN: 53404

Middle Eastern (MID) AF: 0.0835 AC: 481 AN: 5762

European-Non Finnish (NFE) AF: 0.0841 AC: 93263 AN: 1108594

Other (OTH) AF: 0.0869 AC: 5239 AN: 60254

GnomAD4 genome AF: 0.0925 AC: 14084 AN: 152188 Hom.: 645 Cov.: 32 AF XY: 0.0932 AC XY: 6932 AN XY: 74406

African (AFR) AF: 0.109 AC: 4522 AN: 41512

American (AMR) AF: 0.0719 AC: 1100 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0953 AC: 330 AN: 3464

East Asian (EAS) AF: 0.0417 AC: 216 AN: 5180

South Asian (SAS) AF: 0.0807 AC: 389 AN: 4820

European-Finnish (FIN) AF: 0.122 AC: 1287 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0865 AC: 5880 AN: 68008

Other (OTH) AF: 0.0848 AC: 179 AN: 2112

Alfa AF: 0.0867 Hom.: 618

Bravo AF: 0.0903

Asia WGS AF: 0.0530 AC: 184 AN: 3478

EpiCase AF: 0.0887

EpiControl AF: 0.0890

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	RASopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.0080
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: rs41306345; hg19: chr15-66782048; COSMIC: COSV57233926; COSMIC: COSV57233926;