20-2417282-G-C

Variant names:

• chr20-2417282-G-C
• rs138184667
• NM_198994.3:c.1387G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198994.3(TGM6):​c.1387G>C​(p.Gly463Arg) 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 1,459,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300

Genes affected

TGM6 (HGNC:16255): (transglutaminase 6) The protein encoded by this gene belongs to the transglutaminase superfamily. It catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Mutations in this gene are associated with spinocerebellar ataxia type 35 (SCA35). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20492691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM6	NM_198994.3	c.1387G>C	p.Gly463Arg	missense_variant	Exon 10 of 13	ENST00000202625.7	NP_945345.2
TGM6	NM_001254734.2	c.1387G>C	p.Gly463Arg	missense_variant	Exon 10 of 12		NP_001241663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM6	ENST00000202625.7	c.1387G>C	p.Gly463Arg	missense_variant	Exon 10 of 13	1	NM_198994.3	ENSP00000202625.2
TGM6	ENST00000381423.1	c.1387G>C	p.Gly463Arg	missense_variant	Exon 10 of 12	1		ENSP00000370831.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000414 AC: 1 AN: 241714 Hom.: 0 AF XY: 0.00000763 AC XY: 1 AN XY: 131106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459036 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.21
DANN	Benign	0.92
DEOGEN2	Benign	0.0074	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.036	D;D
Polyphen		0.54	P;P
Vest4		0.31
MutPred		0.49		Loss of catalytic residue at V464 (P = 0.025);Loss of catalytic residue at V464 (P = 0.025);
MVP		0.32
MPC		0.11
ClinPred		0.62	D
GERP RS		-9.1
Varity_R		0.11
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs138184667; hg19: chr20-2397928;