2-159878680-C-A

Variant names:

• chr2-159878680-C-A
• rs114727644
• NM_002349.4:c.1557G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002349.4(LY75):​c.1557G>T​(p.Glu519Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,613,926 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (25 hom.)
• Consequence: LY75 NM_002349.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.718
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002149552).
• BP6: Variant 2-159878680-C-A is Benign according to our data. Variant chr2-159878680-C-A is described in ClinVar as Benign. ClinVar VariationId is 791874.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 = 0.0108 (1648/152282) while in subpopulation AFR AF = 0.0379 (1574/41568). AF 95% confidence interval is 0.0363. There are 19 homozygotes in GnomAd4. There are 793 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002349.4. 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
	LY75	NM_002349.4	MANE Select	c.1557G>T	p.Glu519Asp	missense	Exon 10 of 35	NP_002340.2	O60449-1
	LY75-CD302	NM_001198759.1		c.1557G>T	p.Glu519Asp	missense	Exon 10 of 39	NP_001185688.1	O60449-2
	LY75-CD302	NM_001198760.1		c.1557G>T	p.Glu519Asp	missense	Exon 10 of 38	NP_001185689.1	O60449-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LY75	ENST00000263636.5	TSL:1 MANE Select	c.1557G>T	p.Glu519Asp	missense	Exon 10 of 35	ENSP00000263636.4	O60449-1
	LY75-CD302	ENST00000504764.5	TSL:2	c.1557G>T	p.Glu519Asp	missense	Exon 10 of 39	ENSP00000423463.1
	LY75	ENST00000484559.1	TSL:1	n.1617G>T		non_coding_transcript_exon	Exon 10 of 13

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1644 AN: 152164 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00273 AC: 686 AN: 251240 AF XY: 0.00203

Gnomad AFR exome AF: 0.0390

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00102 AC: 1491 AN: 1461644 Hom.: 25 Cov.: 32 AF XY: 0.000839 AC XY: 610 AN XY: 727120

African (AFR) AF: 0.0373 AC: 1247 AN: 33440

American (AMR) AF: 0.00154 AC: 69 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111900

Other (OTH) AF: 0.00224 AC: 135 AN: 60378

GnomAD4 genome AF: 0.0108 AC: 1648 AN: 152282 Hom.: 19 Cov.: 32 AF XY: 0.0107 AC XY: 793 AN XY: 74450

African (AFR) AF: 0.0379 AC: 1574 AN: 41568

American (AMR) AF: 0.00347 AC: 53 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00417 Hom.: 28

Bravo AF: 0.0120

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00344 AC: 418

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.72
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.041
Sift	Benign	0.27	T
Sift4G	Benign	0.43	T
Polyphen		0.34	B
Vest4		0.19
MutPred		0.47		Gain of sheet (P = 0.0827)
MVP		0.15
MPC		0.052
ClinPred		0.00061	T
GERP RS		-1.0
Varity_R		0.13
gMVP		0.45
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs114727644; hg19: chr2-160735191; COSMIC: COSV99717284;