1-100874275-G-C

Variant names:

• chr1-100874275-G-C
• rs199672282
• NM_001033025.3:c.660C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001033025.3(EXTL2):​c.660C>G​(p.Ser220Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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: 32)
• Consequence: EXTL2 NM_001033025.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 1 publications found

Genes affected

EXTL2 (HGNC:3516): (exostosin like glycosyltransferase 2) Enables alpha-1,4-N-acetylgalactosaminyltransferase activity and glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity. Involved in N-acetylglucosamine metabolic process and UDP-N-acetylgalactosamine metabolic process. Located in cytosol; endoplasmic reticulum; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17816979).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033025.3. 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
	EXTL2	NM_001033025.3	MANE Select	c.660C>G	p.Ser220Arg	missense	Exon 5 of 5	NP_001028197.1	Q9UBQ6
	EXTL2	NM_001261441.2		c.684C>G	p.Ser228Arg	missense	Exon 6 of 6	NP_001248370.1
	EXTL2	NM_001439.4		c.660C>G	p.Ser220Arg	missense	Exon 5 of 5	NP_001430.1	Q9UBQ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXTL2	ENST00000370114.8	TSL:1 MANE Select	c.660C>G	p.Ser220Arg	missense	Exon 5 of 5	ENSP00000359132.3	Q9UBQ6
	EXTL2	ENST00000370113.7	TSL:1	c.660C>G	p.Ser220Arg	missense	Exon 5 of 5	ENSP00000359131.3	Q9UBQ6
	EXTL2	ENST00000886545.1		c.684C>G	p.Ser228Arg	missense	Exon 6 of 6	ENSP00000556603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.45	N
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.24
Sift	Benign	0.30	T
Sift4G	Benign	0.76	T
Polyphen		0.032	B
Vest4		0.14
MutPred		0.62		Gain of methylation at K221 (P = 0.0426)
MVP		0.74
MPC		0.18
ClinPred		0.36	T
GERP RS		4.0
Varity_R		0.051
gMVP		0.48
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199672282; hg19: chr1-101339831;