rs8684

Positions:

• chr15-66491272-G-A
• chr15-66491272-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000307102.10(MAP2K1):​c.*657G>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 0.0599 in 237,318 control chromosomes in the GnomAD database, including 586 homozygotes. 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 0.056 (343 hom., cov: 32)
  • Exomes 𝑓: 0.067 (243 hom.)
• Consequence: MAP2K1 ENST00000307102.10 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.848

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]

(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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.*657G>A		3_prime_UTR_variant	11/11	ENST00000307102.10	NP_002746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.*657G>A		3_prime_UTR_variant	11/11	1	NM_002755.4	ENSP00000302486	P1
	ENST00000565387.2	n.109-555C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8556 AN: 152052 Hom.: 342 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0802

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0793

Gnomad OTH AF: 0.0652

GnomAD4 exome AF: 0.0665 AC: 5665 AN: 85148 Hom.: 243 Cov.: 0 AF XY: 0.0671 AC XY: 2654 AN XY: 39574

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.0391

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0229

Gnomad4 FIN exome AF: 0.0785

Gnomad4 NFE exome AF: 0.0818

Gnomad4 OTH exome AF: 0.0774

GnomAD4 genome AF: 0.0562 AC: 8556 AN: 152170 Hom.: 343 Cov.: 32 AF XY: 0.0561 AC XY: 4172 AN XY: 74402

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.0442

Gnomad4 ASJ AF: 0.0931

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0293

Gnomad4 FIN AF: 0.0802

Gnomad4 NFE AF: 0.0793

Gnomad4 OTH AF: 0.0645

Alfa AF: 0.0769 Hom.: 481

Bravo AF: 0.0521

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.94
DANN	Benign	0.51
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

Publications

LitVar

Other links and lift over

dbSNP: rs8684; hg19: chr15-66783610;