6-31269526-C-A

Variant names:

• chr6-31269526-C-A
• NM_002117.6:c.1016-1G>T

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.1016-1G>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 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_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.958
• 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. Cryptic splice site detected, with MaxEntScore 5.3, offset of -18, new splice context is: tcctcccagtcccctcatAGggc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in 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.1016-1G>T		splice_acceptor 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.1016-1G>T		splice_acceptor intron	N/A	ENSP00000365402.5	P10321-1
	HLA-C	ENST00000383329.7	TSL:6	c.1033G>T	p.Gly345Cys	missense	Exon 6 of 8	ENSP00000372819.3	A2AEA2
	HLA-C	ENST00000956155.1		c.1016-1G>T		splice_acceptor intron	N/A	ENSP00000626214.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 64812 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: 827358 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 410390

African (AFR) AF: 0.00 AC: 0 AN: 15220

American (AMR) AF: 0.00 AC: 0 AN: 21582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7862

East Asian (EAS) AF: 0.00 AC: 0 AN: 13350

South Asian (SAS) AF: 0.00 AC: 0 AN: 40620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2106

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 666046

Other (OTH) AF: 0.00 AC: 0 AN: 32618

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 64812 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 30786

African (AFR) AF: 0.00 AC: 0 AN: 12878

American (AMR) AF: 0.00 AC: 0 AN: 5758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 840

East Asian (EAS) AF: 0.00 AC: 0 AN: 1666

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 106

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 35862

Other (OTH) AF: 0.00 AC: 0 AN: 774

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.91
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.022	N
M_CAP	Benign	0.0046	T
PhyloP100		0.96
ClinPred		0.15	T
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
Splicevardb		3.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: -1

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

Other links and lift over

hg19: chr6-31237303; COSMIC: COSV66119135; COSMIC: COSV66119135;