15-67646223-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_145160.3(MAP2K5):c.586-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,168,156 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (7 hom.)
• Consequence: MAP2K5 NM_145160.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004639
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.844

Genes affected

MAP2K5 (HGNC:6845): (mitogen-activated protein kinase kinase 5) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically interacts with and activates MAPK7/ERK5. This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs). The signal cascade mediated by this kinase is involved in growth factor stimulated cell proliferation and muscle cell differentiation. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been described. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-67646223-A-G is Benign according to our data. Variant chr15-67646223-A-G is described in ClinVar as [Benign]. Clinvar id is 776918.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00539 (821/152300) while in subpopulation AFR AF= 0.0186 (772/41562). AF 95% confidence interval is 0.0175. There are 12 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 820 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K5	NM_145160.3	c.586-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000178640.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K5	ENST00000178640.10	c.586-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_145160.3	P1

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 820 AN: 152182 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00154 AC: 234 AN: 151942 Hom.: 4 AF XY: 0.00133 AC XY: 109 AN XY: 81986

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.000253

GnomAD4 exome AF: 0.000517 AC: 525 AN: 1015856 Hom.: 7 Cov.: 13 AF XY: 0.000470 AC XY: 243 AN XY: 517138

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000315

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000160

Gnomad4 OTH exome AF: 0.000966

GnomAD4 genome AF: 0.00539 AC: 821 AN: 152300 Hom.: 12 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74474

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.00582

Asia WGS AF: 0.000579 AC: 2 AN: 3470

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

Jan 19, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.7
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0
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: rs28580436; hg19: chr15-67938561;