2-159898829-T-G

Position:

• chr2-159898829-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002349.4(LY75):​c.325A>C​(p.Lys109Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,614,182 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (4 hom.)
• Consequence: LY75 NM_002349.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051385164).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LY75	NM_002349.4	c.325A>C	p.Lys109Gln	missense_variant	2/35	ENST00000263636.5	NP_002340.2
LY75-CD302	NM_001198759.1	c.325A>C	p.Lys109Gln	missense_variant	2/39		NP_001185688.1
LY75-CD302	NM_001198760.1	c.325A>C	p.Lys109Gln	missense_variant	2/38		NP_001185689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LY75	ENST00000263636.5	c.325A>C	p.Lys109Gln	missense_variant	2/35	1	NM_002349.4	ENSP00000263636.4
LY75-CD302	ENST00000504764.5	c.325A>C	p.Lys109Gln	missense_variant	2/39	2		ENSP00000423463.1
LY75	ENST00000484559.1	n.385A>C		non_coding_transcript_exon_variant	2/13	1
LY75-CD302	ENST00000505052.1	c.325A>C	p.Lys109Gln	missense_variant	2/38	2		ENSP00000421035.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152174 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251430 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135890

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1461890 Hom.: 4 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 727246

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152292 Hom.: 1 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74478

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.325A>C (p.K109Q) alteration is located in exon 2 (coding exon 2) of the LY75 gene. This alteration results from a A to C substitution at nucleotide position 325, causing the lysine (K) at amino acid position 109 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	.;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.6	.;.;M
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.44
MVP		0.59
MPC		0.34
ClinPred		0.049	T
GERP RS		5.9
Varity_R		0.53
gMVP		0.59

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: rs150493510; hg19: chr2-160755340;