11-45926499-TTC-CTT

Variant names:

• chr11-45926499-TTC-CTT
• NM_001300721.2:c.1066_1068delTTCinsCTT
• LARGE2 p.Phe356Leu

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001300721.2(LARGE2):​c.1066_1068delTTCinsCTT​(p.Phe356Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LARGE2 NM_001300721.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

LARGE2 (HGNC:16522): (LARGE xylosyl- and glucuronyltransferase 2) Predicted to enable dystroglycan binding activity; glucuronosyltransferase activity; and xylosyltransferase activity. Involved in protein O-linked mannosylation. Predicted to be located in intracellular membrane-bounded organelle. Predicted to be active in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300721.2. 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
	LARGE2	NM_001300721.2	MANE Select	c.1066_1068delTTCinsCTT	p.Phe356Leu	missense	N/A	NP_001287650.1	Q8N3Y3
	LARGE2	NM_152312.5		c.1066_1068delTTCinsCTT	p.Phe356Leu	missense	N/A	NP_689525.3
	LARGE2	NM_001300722.2		c.973_975delTTCinsCTT	p.Phe325Leu	missense	N/A	NP_001287651.1	E9PIZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE2	ENST00000401752.6	TSL:1 MANE Select	c.1066_1068delTTCinsCTT	p.Phe356Leu	missense	N/A	ENSP00000385235.1	Q8N3Y3
	LARGE2	ENST00000325468.9	TSL:1	c.1066_1068delTTCinsCTT	p.Phe356Leu	missense	N/A	ENSP00000324570.5	Q8N3Y3
	LARGE2	ENST00000530437.5	TSL:1	n.137_139delTTCinsCTT		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-45948050;