rs1051788

Positions:

• chr6-31506223-G-A
• chr6-31506223-G-C
• chr6-31506223-G-T

Variant summary

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

The NM_005931.5(MICB):​c.406G>A​(p.Asp136Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,613,810 control chromosomes in the GnomAD database, including 76,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D136H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (7768 hom., cov: 32)
  • Exomes 𝑓: 0.30 (69212 hom.)
• Consequence: MICB NM_005931.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.615

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043391287).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICB	NM_005931.5	c.406G>A	p.Asp136Asn	missense_variant	3/6	ENST00000252229.7
MICB	NM_001289160.2	c.310G>A	p.Asp104Asn	missense_variant	3/6
MICB	NM_001289161.2	c.326-49G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICB	ENST00000252229.7	c.406G>A	p.Asp136Asn	missense_variant	3/6	1	NM_005931.5	P1
MICB	ENST00000399150.7	c.326-49G>A		intron_variant		1
MICB	ENST00000538442.5	c.310G>A	p.Asp104Asn	missense_variant	3/6	2
MICB	ENST00000494577.1	n.289G>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47742 AN: 151852 Hom.: 7759 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.301

GnomAD3 exomes AF: 0.293 AC: 72991 AN: 249430 Hom.: 11442 AF XY: 0.299 AC XY: 40503 AN XY: 135346

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.356

Gnomad EAS exome AF: 0.275

Gnomad SAS exome AF: 0.302

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.304 AC: 444598 AN: 1461840 Hom.: 69212 Cov.: 56 AF XY: 0.306 AC XY: 222666 AN XY: 727206

Gnomad4 AFR exome AF: 0.378

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.356

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.313

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.314 AC: 47784 AN: 151970 Hom.: 7768 Cov.: 32 AF XY: 0.310 AC XY: 22997 AN XY: 74296

Gnomad4 AFR AF: 0.372

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.367

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.298

Alfa AF: 0.296 Hom.: 3169

Bravo AF: 0.313

TwinsUK AF: 0.321 AC: 1190

ALSPAC AF: 0.301 AC: 1161

ESP6500AA AF: 0.368 AC: 1409

ESP6500EA AF: 0.307 AC: 2523

ExAC AF: 0.302 AC: 36524

Asia WGS AF: 0.303 AC: 1055 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.3
DANN	Benign	0.86
DEOGEN2	Benign	0.071	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.058
Sift	Benign	0.33	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.077	B;.
Vest4		0.079
MPC		0.26
ClinPred		0.017	T
GERP RS		-0.60
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1051788; hg19: chr6-31474000; COSMIC: COSV52856573;