2-159805099-C-G

Variant names:

• chr2-159805099-C-G
• rs34034503
• NM_002349.4:c.5114G>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002349.4(LY75):​c.5114G>C​(p.Arg1705Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,068 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: LY75 NM_002349.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.31

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041396767).
• BP6: Variant 2-159805099-C-G is Benign according to our data. Variant chr2-159805099-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2651459.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LY75	NM_002349.4	c.5114G>C	p.Arg1705Pro	missense_variant	Exon 35 of 35	ENST00000263636.5	NP_002340.2
LY75-CD302	NM_001198759.1	c.4990+1874G>C		intron_variant	Intron 34 of 38		NP_001185688.1
LY75-CD302	NM_001198760.1	c.4822+3350G>C		intron_variant	Intron 33 of 37		NP_001185689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LY75	ENST00000263636.5	c.5114G>C	p.Arg1705Pro	missense_variant	Exon 35 of 35	1	NM_002349.4	ENSP00000263636.4
LY75-CD302	ENST00000504764.5	c.4990+1874G>C		intron_variant	Intron 34 of 38	2		ENSP00000423463.1
LY75-CD302	ENST00000505052.1	c.4822+3350G>C		intron_variant	Intron 33 of 37	2		ENSP00000421035.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000780 AC: 196 AN: 251220 Hom.: 1 AF XY: 0.000832 AC XY: 113 AN XY: 135818

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00140 AC: 2048 AN: 1461794 Hom.: 4 Cov.: 30 AF XY: 0.00134 AC XY: 976 AN XY: 727206

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74456

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000986 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000733 AC: 89

EpiCase AF: 0.00120

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5114G>C (p.R1705P) alteration is located in exon 35 (coding exon 35) of the LY75 gene. This alteration results from a G to C substitution at nucleotide position 5114, causing the arginine (R) at amino acid position 1705 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LY75: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.26
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.013	D
Polyphen		0.80	P
Vest4		0.66
MVP		0.39
ClinPred		0.044	T
GERP RS		4.8
Varity_R		0.41
gMVP		0.89

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: rs34034503; hg19: chr2-160661610;