rs34466404

Variant names:

• chr1-235759223-T-C
• rs34466404
• NM_000081.4:c.6630A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000081.4(LYST):​c.6630A>G​(p.Glu2210Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,094 control chromosomes in the GnomAD database, including 1,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (758 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (627 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.04
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-235759223-T-C is Benign according to our data. Variant chr1-235759223-T-C is described in ClinVar as Benign. ClinVar VariationId is 254932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

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.6630A>G	p.Glu2210Glu	synonymous	Exon 23 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.6630A>G	p.Glu2210Glu	synonymous	Exon 23 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.6630A>G	p.Glu2210Glu	synonymous	Exon 23 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000489585.5	TSL:1	n.*464A>G		non_coding_transcript_exon	Exon 23 of 23	ENSP00000513166.1	Q99698-2
	LYST	ENST00000489585.5	TSL:1	n.*464A>G		3_prime_UTR	Exon 23 of 23	ENSP00000513166.1	Q99698-2

Frequencies

GnomAD3 genomes AF: 0.0541 AC: 8229 AN: 152122 Hom.: 755 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0143 AC: 3586 AN: 250970 AF XY: 0.0106

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000732

Gnomad OTH exome AF: 0.00914

GnomAD4 exome AF: 0.00571 AC: 8348 AN: 1461854 Hom.: 627 Cov.: 33 AF XY: 0.00504 AC XY: 3662 AN XY: 727226

African (AFR) AF: 0.191 AC: 6408 AN: 33478

American (AMR) AF: 0.0104 AC: 467 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5766

European-Non Finnish (NFE) AF: 0.000487 AC: 541 AN: 1111998

Other (OTH) AF: 0.0130 AC: 785 AN: 60394

GnomAD4 genome AF: 0.0542 AC: 8254 AN: 152240 Hom.: 758 Cov.: 32 AF XY: 0.0524 AC XY: 3901 AN XY: 74430

African (AFR) AF: 0.188 AC: 7795 AN: 41510

American (AMR) AF: 0.0205 AC: 313 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68032

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0245 Hom.: 212

Bravo AF: 0.0617

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Chédiak-Higashi syndrome (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.55
PhyloP100		-2.0
Mutation Taster		=99/1	polymorphism (auto)

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: rs34466404; hg19: chr1-235922523;