2-159872571-A-G

Position:

• chr2-159872571-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002349.4(LY75):​c.1997T>C​(p.Val666Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,756 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (24 hom.)
• Consequence: LY75 NM_002349.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.36

Genes affected

LY75 (HGNC:6729): (lymphocyte antigen 75) Predicted to enable signaling receptor activity. Predicted to be involved in immune response and inflammatory response. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

LY75-CD302 (HGNC:38828): (LY75-CD302 readthrough) This locus represents naturally occurring read-through transcription between the neighboring lymphocyte antigen 75 (LY75) and CD302 molecule (CD302) genes. Alternative splicing results in multiple transcript variants encoding fusion products that share sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

LY75 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003575623).
• BP6: Variant 2-159872571-A-G is Benign according to our data. Variant chr2-159872571-A-G is described in ClinVar as [Benign]. Clinvar id is 791153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1671/152294) while in subpopulation AFR AF= 0.0375 (1559/41564). AF 95% confidence interval is 0.036. There are 29 homozygotes in gnomad4. There are 795 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LY75	NM_002349.4	c.1997T>C	p.Val666Ala	missense_variant	13/35	ENST00000263636.5	NP_002340.2
LY75-CD302	NM_001198759.1	c.1997T>C	p.Val666Ala	missense_variant	13/39		NP_001185688.1
LY75-CD302	NM_001198760.1	c.1997T>C	p.Val666Ala	missense_variant	13/38		NP_001185689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LY75	ENST00000263636.5	c.1997T>C	p.Val666Ala	missense_variant	13/35	1	NM_002349.4	ENSP00000263636.4
LY75-CD302	ENST00000504764.5	c.1997T>C	p.Val666Ala	missense_variant	13/39	2		ENSP00000423463.1
LY75	ENST00000484559.1	n.2057T>C		non_coding_transcript_exon_variant	13/13	1
LY75-CD302	ENST00000505052.1	c.1997T>C	p.Val666Ala	missense_variant	13/38	2		ENSP00000421035.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1657 AN: 152176 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00277 AC: 694 AN: 250910 Hom.: 9 AF XY: 0.00195 AC XY: 265 AN XY: 135598

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00116 AC: 1696 AN: 1461462 Hom.: 24 Cov.: 31 AF XY: 0.00100 AC XY: 728 AN XY: 727044

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.0110 AC: 1671 AN: 152294 Hom.: 29 Cov.: 32 AF XY: 0.0107 AC XY: 795 AN XY: 74464

Gnomad4 AFR AF: 0.0375

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00203 Hom.: 11

Bravo AF: 0.0133

ESP6500AA AF: 0.0388 AC: 171

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00325 AC: 395

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0083
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;.;M
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.086
Sift	Benign	0.065	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.065	.;.;B
Vest4		0.10
MVP		0.072
MPC		0.33
ClinPred		0.025	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.29

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: rs34020639; hg19: chr2-160729082;