rs2269715

Positions:

• chr1-158255229-C-G
• chr1-158255229-C-T

Variant summary

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

The NM_001763.3(CD1A):​c.204C>G​(p.Cys68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0801 in 1,613,996 control chromosomes in the GnomAD database, including 8,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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.

• Frequency:
  • Genomes: 𝑓 0.076 (808 hom., cov: 31)
  • Exomes 𝑓: 0.081 (7612 hom.)
• Consequence: CD1A NM_001763.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140

Genes affected

CD1A (HGNC:1634): (CD1a molecule) This gene encodes a member of the CD1 family of transmembrane glycoproteins, which are structurally related to the major histocompatibility complex (MHC) proteins and form heterodimers with beta-2-microglobulin. The CD1 proteins mediate the presentation of primarily lipid and glycolipid antigens of self or microbial origin to T cells. The human genome contains five CD1 family genes organized in a cluster on chromosome 1. The CD1 family members are thought to differ in their cellular localization and specificity for particular lipid ligands. The protein encoded by this gene localizes to the plasma membrane and to recycling vesicles of the early endocytic system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.8843703E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD1A	NM_001763.3	c.204C>G	p.Cys68Trp	missense_variant	2/6	ENST00000289429.6	NP_001754.2
CD1A	NM_001320652.2	c.171C>G	p.Cys57Trp	missense_variant	2/6		NP_001307581.1
CD1A	XM_024450738.2	c.-265C>G		5_prime_UTR_variant	3/7		XP_024306506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD1A	ENST00000289429.6	c.204C>G	p.Cys68Trp	missense_variant	2/6	1	NM_001763.3	ENSP00000289429.5

Frequencies

GnomAD3 genomes AF: 0.0763 AC: 11592 AN: 152016 Hom.: 810 Cov.: 31

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0717

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0589

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.111 AC: 27906 AN: 251456 Hom.: 2687 AF XY: 0.114 AC XY: 15555 AN XY: 135904

Gnomad AFR exome AF: 0.0524

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.0824

Gnomad EAS exome AF: 0.371

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.0726

Gnomad NFE exome AF: 0.0569

Gnomad OTH exome AF: 0.0862

GnomAD4 exome AF: 0.0806 AC: 117756 AN: 1461862 Hom.: 7612 Cov.: 33 AF XY: 0.0843 AC XY: 61287 AN XY: 727230

Gnomad4 AFR exome AF: 0.0542

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.0825

Gnomad4 EAS exome AF: 0.336

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.0724

Gnomad4 NFE exome AF: 0.0598

Gnomad4 OTH exome AF: 0.0884

GnomAD4 genome AF: 0.0763 AC: 11602 AN: 152134 Hom.: 808 Cov.: 31 AF XY: 0.0813 AC XY: 6044 AN XY: 74366

Gnomad4 AFR AF: 0.0517

Gnomad4 AMR AF: 0.0720

Gnomad4 ASJ AF: 0.0844

Gnomad4 EAS AF: 0.378

Gnomad4 SAS AF: 0.248

Gnomad4 FIN AF: 0.0727

Gnomad4 NFE AF: 0.0589

Gnomad4 OTH AF: 0.0554

Alfa AF: 0.0628 Hom.: 323

Bravo AF: 0.0727

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0615 AC: 237

ESP6500AA AF: 0.0508 AC: 224

ESP6500EA AF: 0.0577 AC: 496

ExAC AF: 0.110 AC: 13309

Asia WGS AF: 0.260 AC: 901 AN: 3478

EpiCase AF: 0.0573

EpiControl AF: 0.0572

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.3
DANN	Benign	0.56
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00040	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.00089	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.7	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	4.5	N
REVEL	Benign	0.034
Sift	Benign	0.19	T
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.043
ClinPred		0.0036	T
GERP RS		-1.9
Varity_R		0.083
gMVP		0.46

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: rs2269715; hg19: chr1-158225019; COSMIC: COSV56860848;