rs1062225

Variant names:

• chr10-48435183-A-G
• rs1062225
• ENST00000469110.1:n.2338A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000469110.1(MAPK8):​n.2338A>G variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0986 in 559,926 control chromosomes in the GnomAD database, including 3,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (771 hom., cov: 32)
  • Exomes 𝑓: 0.10 (2670 hom.)
• Consequence: MAPK8 ENST00000469110.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.92
• Publications: 12 publications found

Genes affected

MAPK8 (HGNC:6881): (mitogen-activated protein kinase 8) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various cell stimuli, and targets specific transcription factors, and thus mediates immediate-early gene expression in response to cell stimuli. The activation of this kinase by tumor-necrosis factor alpha (TNF-alpha) is found to be required for TNF-alpha induced apoptosis. This kinase is also involved in UV radiation induced apoptosis, which is thought to be related to cytochrom c-mediated cell death pathway. Studies of the mouse counterpart of this gene suggested that this kinase play a key role in T cell proliferation, apoptosis and differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Apr 2016]

ARHGAP22 (HGNC:30320): (Rho GTPase activating protein 22) This gene encodes a member of the GTPase activating protein family which activates a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues. The result of these interactions is regulation of cell motility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 10-48435183-A-G is Benign according to our data. Variant chr10-48435183-A-G is described in ClinVar as Benign. ClinVar VariationId is 1276513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK8	NM_001323329.2	c.*154A>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000374189.6	NP_001310258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK8	ENST00000374189.6	c.*154A>G		3_prime_UTR_variant	Exon 12 of 12	5	NM_001323329.2	ENSP00000363304.1

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12915 AN: 152098 Hom.: 772 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0633

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.104 AC: 42276 AN: 407710 Hom.: 2670 Cov.: 6 AF XY: 0.102 AC XY: 21337 AN XY: 209738

African (AFR) AF: 0.0212 AC: 229 AN: 10780

American (AMR) AF: 0.0585 AC: 671 AN: 11464

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 1320 AN: 11656

East Asian (EAS) AF: 0.000224 AC: 6 AN: 26796

South Asian (SAS) AF: 0.0316 AC: 732 AN: 23192

European-Finnish (FIN) AF: 0.138 AC: 3571 AN: 25802

Middle Eastern (MID) AF: 0.116 AC: 202 AN: 1748

European-Non Finnish (NFE) AF: 0.122 AC: 33222 AN: 273006

Other (OTH) AF: 0.0998 AC: 2323 AN: 23266

GnomAD4 genome AF: 0.0848 AC: 12911 AN: 152216 Hom.: 771 Cov.: 32 AF XY: 0.0847 AC XY: 6300 AN XY: 74414

African (AFR) AF: 0.0230 AC: 956 AN: 41554

American (AMR) AF: 0.0633 AC: 967 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4816

European-Finnish (FIN) AF: 0.150 AC: 1588 AN: 10570

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8491 AN: 68014

Other (OTH) AF: 0.0919 AC: 194 AN: 2112

Alfa AF: 0.115 Hom.: 1584

Bravo AF: 0.0776

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2021

GeneDx

Significance: 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	-0.37
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		3.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs1062225; hg19: chr10-49643226;