6-31507234-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005931.5(MICB):c.826G>A(p.Glu276Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MICB NM_005931.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0420

Genes affected

MICB (HGNC:7091): (MHC class I polypeptide-related sequence B) This gene encodes a heavily glycosylated protein which is a ligand for the NKG2D type II receptor. Binding of the ligand activates the cytolytic response of natural killer (NK) cells, CD8 alphabeta T cells, and gammadelta T cells which express the receptor. This protein is stress-induced and is similar to MHC class I molecules; however, it does not associate with beta-2-microglobulin or bind peptides. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11892453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICB	NM_005931.5	c.826G>A	p.Glu276Lys	missense_variant	4/6	ENST00000252229.7
MICB	NM_001289160.2	c.730G>A	p.Glu244Lys	missense_variant	4/6
MICB	NM_001289161.2	c.697G>A	p.Glu233Lys	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICB	ENST00000252229.7	c.826G>A	p.Glu276Lys	missense_variant	4/6	1	NM_005931.5	P1
MICB	ENST00000399150.7	c.697G>A	p.Glu233Lys	missense_variant	4/6	1
MICB	ENST00000538442.5	c.730G>A	p.Glu244Lys	missense_variant	4/6	2
MICB	ENST00000494577.1	n.709G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249358 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

The c.826G>A (p.E276K) alteration is located in exon 4 (coding exon 4) of the MICB gene. This alteration results from a G to A substitution at nucleotide position 826, causing the glutamic acid (E) at amino acid position 276 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.045	N
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.093
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.0070	B;.;.
Vest4		0.15
MutPred		0.59		.;.;Gain of methylation at E276 (P = 0.0038);
MVP		0.31
MPC		0.30
ClinPred		0.13	T
GERP RS		2.7
gMVP		0.35

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: rs750745803; hg19: chr6-31475011;