rs17722172

Variant names:

• chr22-33274598-G-A
• rs17722172
• NM_133642.5:c.2100C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-33274598-G-A
• chr22-33274598-G-C

Variant summary

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

The NM_133642.5(LARGE1):​c.2100C>T​(p.Asn700Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0598 in 1,613,914 control chromosomes in the GnomAD database, including 3,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (220 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3023 hom.)
• Consequence: LARGE1 NM_133642.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.165
• Publications: 8 publications found

Genes affected

LARGE1 (HGNC:6511): (LARGE xylosyl- and glucuronyltransferase 1) This gene encodes a member of the N-acetylglucosaminyltransferase gene family. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. The protein encoded by this gene is the glycotransferase that adds the final xylose and glucuronic acid to alpha-dystroglycan and thereby allows alpha-dystroglycan to bind ligands including laminin 211 and neurexin. Mutations in this gene cause several forms of congenital muscular dystrophy characterized by cognitive disability and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2018]

LARGE1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy type B6

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  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=-0.61).
• BP6: Variant 22-33274598-G-A is Benign according to our data. Variant chr22-33274598-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133642.5. 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
	LARGE1	NM_133642.5	MANE Select	c.2100C>T	p.Asn700Asn	synonymous	Exon 15 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.2100C>T	p.Asn700Asn	synonymous	Exon 16 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.2100C>T	p.Asn700Asn	synonymous	Exon 15 of 15	NP_001349880.1	O95461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.2100C>T	p.Asn700Asn	synonymous	Exon 15 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.2100C>T	p.Asn700Asn	synonymous	Exon 16 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.1944C>T	p.Asn648Asn	synonymous	Exon 14 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7044 AN: 152122 Hom.: 220 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0706

Gnomad AMR AF: 0.0557

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.0564

GnomAD2 exomes AF: 0.0472 AC: 11842 AN: 250860 AF XY: 0.0477

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0807

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0390

Gnomad NFE exome AF: 0.0696

Gnomad OTH exome AF: 0.0626

GnomAD4 exome AF: 0.0612 AC: 89503 AN: 1461674 Hom.: 3023 Cov.: 31 AF XY: 0.0603 AC XY: 43876 AN XY: 727178

African (AFR) AF: 0.0111 AC: 370 AN: 33480

American (AMR) AF: 0.0352 AC: 1573 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 2086 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0198 AC: 1712 AN: 86252

European-Finnish (FIN) AF: 0.0443 AC: 2367 AN: 53420

Middle Eastern (MID) AF: 0.0723 AC: 417 AN: 5768

European-Non Finnish (NFE) AF: 0.0695 AC: 77272 AN: 1111808

Other (OTH) AF: 0.0613 AC: 3703 AN: 60386

GnomAD4 genome AF: 0.0463 AC: 7042 AN: 152240 Hom.: 220 Cov.: 32 AF XY: 0.0436 AC XY: 3245 AN XY: 74426

African (AFR) AF: 0.0127 AC: 528 AN: 41564

American (AMR) AF: 0.0555 AC: 848 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 301 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4810

European-Finnish (FIN) AF: 0.0350 AC: 371 AN: 10606

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0693 AC: 4714 AN: 68004

Other (OTH) AF: 0.0563 AC: 119 AN: 2114

Alfa AF: 0.0620 Hom.: 633

Bravo AF: 0.0456

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Muscular dystrophy-dystroglycanopathy type B6 (2)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.8
DANN	Benign	0.89
PhyloP100		-0.17
Mutation Taster		=94/6	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: rs17722172; hg19: chr22-33670584;