Genetic Variant NM_001075.6:c.664T>C (chr4-68816683-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001075.6(UGT2B10):c.664T>C(p.Trp222Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,628 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

UGT2B10
NM_001075.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.408

Variant links:

Genes affected

UGT2B10 (HGNC:12544): (UDP glucuronosyltransferase family 2 member B10) Predicted to be involved in lipid metabolic process. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

UGT2B10 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT2B10	NM_001075.6 link	c.664T>C	p.Trp222Arg	missense_variant	Exon 1 of 6	ENST00000265403.12	NP_001066.1	P36537-1
UGT2B10	XM_017008585.3 link	c.664T>C	p.Trp222Arg	missense_variant	Exon 1 of 6		XP_016864074.1
UGT2B10	NM_001144767.3 link	c.466+198T>C		intron_variant	Intron 1 of 5		NP_001138239.1	P36537-2
UGT2B10	NM_001290091.2 link	c.-27+511T>C		intron_variant	Intron 1 of 5		NP_001277020.1	P36537

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT2B10	ENST00000265403.12 link	c.664T>C	p.Trp222Arg	missense_variant	Exon 1 of 6	1	NM_001075.6	ENSP00000265403.7		P36537-1
UGT2B10	ENST00000458688.2 link	c.466+198T>C		intron_variant	Intron 1 of 5	2		ENSP00000413420.2		P36537-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.664T>C (p.W222R) alteration is located in exon 1 (coding exon 1) of the UGT2B10 gene. This alteration results from a T to C substitution at nucleotide position 664, causing the tryptophan (W) at amino acid position 222 to be replaced by an arginine (R). 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

Uncertain

0.46

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.099

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.32

M_CAP

Benign

0.0056

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.2

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-11

REVEL

Benign

0.17

Sift

Uncertain

0.015

Sift4G

Benign

0.37

Polyphen

0.86

Vest4

0.37

MutPred

0.61

Gain of methylation at W222 (P = 0.0667);

MVP

0.42

MPC

0.029

ClinPred

0.89

GERP RS

1.4

Varity_R

0.26

gMVP

0.65

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over