NM_002117.6:c.1048+2T>G

Variant names:

• chr6-31269491-A-C
• NM_002117.6:c.1048+2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_002117.6(HLA-C):​c.1048+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 4)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.35
• Publications: 0 publications found

Genes affected

HLA-C (HGNC:4933): (major histocompatibility complex, class I, C) HLA-C 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 endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, 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. About 6000 HLA-C alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029972753 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002117.6. 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-C	NM_002117.6	MANE Select	c.1048+2T>G		splice_donor intron	N/A	NP_002108.4	P10321-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.1048+2T>G		splice_donor intron	N/A	ENSP00000365402.5	P10321-1
	HLA-C	ENST00000956155.1		c.1050T>G	p.Cys350Trp	missense splice_region	Exon 6 of 8	ENSP00000626214.1
	HLA-C	ENST00000383329.7	TSL:6	c.1066+2T>G		splice_donor intron	N/A	ENSP00000372819.3	A2AEA2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 64888 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 843308 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 418252

African (AFR) AF: 0.00 AC: 0 AN: 16048

American (AMR) AF: 0.00 AC: 0 AN: 22142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8242

East Asian (EAS) AF: 0.00 AC: 0 AN: 13788

South Asian (SAS) AF: 0.00 AC: 0 AN: 42258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2200

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 676942

Other (OTH) AF: 0.00 AC: 0 AN: 33290

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 64888 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 30842

African (AFR) AF: 0.00 AC: 0 AN: 12926

American (AMR) AF: 0.00 AC: 0 AN: 5776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 856

East Asian (EAS) AF: 0.00 AC: 0 AN: 1668

South Asian (SAS) AF: 0.00 AC: 0 AN: 1738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 102

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 35878

Other (OTH) AF: 0.00 AC: 0 AN: 766

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	23
DANN	Benign	0.41
Eigen	Benign	0.10
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.23	N
PhyloP100		3.4
GERP RS		0.32
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.68
Splicevardb		3.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr6-31237268; COSMIC: COSV66118863; COSMIC: COSV66118863;