10-48434924-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001323329.2(MAPK8):c.1179G>A(p.Ser393=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,613,296 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: MAPK8 NM_001323329.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40

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:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-48434924-G-A is Benign according to our data. Variant chr10-48434924-G-A is described in ClinVar as [Benign]. Clinvar id is 778386.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00107 (1560/1461286) while in subpopulation AMR AF= 0.0269 (1203/44644). AF 95% confidence interval is 0.0257. There are 25 homozygotes in gnomad4_exome. There are 688 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 296 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8	NM_001323329.2	c.1179G>A	p.Ser393=	synonymous_variant	12/12	ENST00000374189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8	ENST00000374189.6	c.1179G>A	p.Ser393=	synonymous_variant	12/12	5	NM_001323329.2	A1

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 151892 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000823

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00450 AC: 1129 AN: 250840 Hom.: 18 AF XY: 0.00346 AC XY: 469 AN XY: 135616

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.0298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00107 AC: 1560 AN: 1461286 Hom.: 25 Cov.: 32 AF XY: 0.000946 AC XY: 688 AN XY: 726952

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152010 Hom.: 4 Cov.: 31 AF XY: 0.00234 AC XY: 174 AN XY: 74280

Gnomad4 AFR AF: 0.000820

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000705 Hom.: 0

Bravo AF: 0.00409

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.4
Dann	Benign	0.79

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: rs142330800; hg19: chr10-49642967; COSMIC: COSV64408809; COSMIC: COSV64408809;