rs140434436

Variant names:

• chr1-235752126-T-C
• rs140434436
• NM_000081.4:c.7506A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-235752126-T-C
• chr1-235752126-T-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BS1 BS2

The NM_000081.4(LYST):​c.7506A>G​(p.Gln2502Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000829 in 1,612,156 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 0.226
• Publications: 2 publications found

Genes affected

LYST (HGNC:1968): (lysosomal trafficking regulator) This gene encodes a protein that regulates intracellular protein trafficking in endosomes, and may be involved in pigmentation. Mutations in this gene are associated with Chediak-Higashi syndrome, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants, though the full-length nature of some of these variants has not been determined. [provided by RefSeq, Apr 2013]

LYST Gene-Disease associations (from GenCC):

• Chediak-Higashi syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp
• attenuated Chédiak-Higashi syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-235752126-T-C is Benign according to our data. Variant chr1-235752126-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254939.
• BP7: Synonymous conserved (PhyloP=0.226 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00108 (165/152266) while in subpopulation AMR AF = 0.00399 (61/15296). AF 95% confidence interval is 0.00319. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000081.4. 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
	LYST	NM_000081.4	MANE Select	c.7506A>G	p.Gln2502Gln	synonymous	Exon 27 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.7506A>G	p.Gln2502Gln	synonymous	Exon 27 of 53	NP_001288294.1	Q99698-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.7506A>G	p.Gln2502Gln	synonymous	Exon 27 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697241.1		c.1986A>G	p.Gln662Gln	synonymous	Exon 11 of 26	ENSP00000513206.1	A0A8V8TM69
	LYST	ENST00000487530.2	TSL:4	c.45A>G	p.Gln15Gln	synonymous	Exon 1 of 4	ENSP00000417168.1	H7C4F5

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00117 AC: 293 AN: 250672 AF XY: 0.00128

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000936

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.000803 AC: 1172 AN: 1459890 Hom.: 2 Cov.: 29 AF XY: 0.000862 AC XY: 626 AN XY: 726352

African (AFR) AF: 0.000240 AC: 8 AN: 33400

American (AMR) AF: 0.00208 AC: 93 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00613 AC: 160 AN: 26102

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39570

South Asian (SAS) AF: 0.00130 AC: 112 AN: 86198

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53324

Middle Eastern (MID) AF: 0.00952 AC: 54 AN: 5670

European-Non Finnish (NFE) AF: 0.000589 AC: 654 AN: 1110670

Other (OTH) AF: 0.00144 AC: 87 AN: 60264

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74450

African (AFR) AF: 0.000168 AC: 7 AN: 41572

American (AMR) AF: 0.00399 AC: 61 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 67988

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000972 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.000578 AC: 2 AN: 3472

EpiCase AF: 0.00175

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	Chédiak-Higashi syndrome (3)
-	-	2	not provided (2)
-	1	-	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.2
DANN	Benign	0.41
PhyloP100		0.23
PromoterAI		0.017	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs140434436; hg19: chr1-235915426;