rs2257269

Variant names:

• chr6-31355576-G-A
• rs2257269
• NM_005514.8:c.636C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-31355576-G-A
• chr6-31355576-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_005514.8(HLA-B):​c.636C>T​(p.His212His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (909 hom., cov: 9)
  • Exomes 𝑓: 0.24 (63392 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26
• Publications: 21 publications found

Genes affected

HLA-B (HGNC:4932): (major histocompatibility complex, class I, B) HLA-B belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exon 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]

ENSG00000298396 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005514.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	NM_005514.8	MANE Select	c.636C>T	p.His212His	synonymous	Exon 4 of 8	NP_005505.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.636C>T	p.His212His	synonymous	Exon 4 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.636C>T	p.His212His	synonymous	Exon 7 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.636C>T	p.His212His	synonymous	Exon 6 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 10072 AN: 64482 Hom.: 908 Cov.: 9

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0851

Gnomad FIN AF: 0.0894

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.400 AC: 100383 AN: 250894 AF XY: 0.394

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.490

Gnomad EAS exome AF: 0.366

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.419

Gnomad OTH exome AF: 0.435

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.244 AC: 245885 AN: 1006204 Hom.: 63392 Cov.: 31 AF XY: 0.247 AC XY: 125274 AN XY: 507318

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.290 AC: 6958 AN: 23990

American (AMR) AF: 0.357 AC: 12441 AN: 34822

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 8196 AN: 19716

East Asian (EAS) AF: 0.209 AC: 6483 AN: 31000

South Asian (SAS) AF: 0.232 AC: 16519 AN: 71246

European-Finnish (FIN) AF: 0.207 AC: 8586 AN: 41524

Middle Eastern (MID) AF: 0.253 AC: 989 AN: 3902

European-Non Finnish (NFE) AF: 0.236 AC: 173677 AN: 737418

Other (OTH) AF: 0.283 AC: 12036 AN: 42586

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.156 AC: 10087 AN: 64572 Hom.: 909 Cov.: 9 AF XY: 0.147 AC XY: 4522 AN XY: 30772

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.120 AC: 1691 AN: 14088

American (AMR) AF: 0.167 AC: 870 AN: 5216

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 512 AN: 1562

East Asian (EAS) AF: 0.101 AC: 213 AN: 2102

South Asian (SAS) AF: 0.0845 AC: 130 AN: 1538

European-Finnish (FIN) AF: 0.0894 AC: 432 AN: 4832

Middle Eastern (MID) AF: 0.196 AC: 22 AN: 112

European-Non Finnish (NFE) AF: 0.177 AC: 6025 AN: 34030

Other (OTH) AF: 0.153 AC: 105 AN: 688

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.405 Hom.: 5293

Asia WGS AF: 0.366 AC: 1274 AN: 3478

EpiCase AF: 0.428

EpiControl AF: 0.438

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.2
DANN	Benign	0.45
PhyloP100		-2.3
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2257269; hg19: chr6-31323353; COSMIC: COSV69521382; COSMIC: COSV69521382;