2-19901771-C-G

Position:

• chr2-19901771-C-G

Variant summary

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

The NM_001008237.3(TTC32):​c.84G>C​(p.Glu28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: TTC32 NM_001008237.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.141

Genes affected

TTC32 (HGNC:32954): (tetratricopeptide repeat domain 32)

ACMG classification

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/exons	MANE	Protein	UniProt
TTC32	NM_001008237.3	c.84G>C	p.Glu28Asp	missense_variant	1/3	ENST00000333610.4	NP_001008238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC32	ENST00000333610.4	c.84G>C	p.Glu28Asp	missense_variant	1/3	1	NM_001008237.3	ENSP00000333018.3
TTC32	ENST00000402414.1	c.84G>C	p.Glu28Asp	missense_variant	1/2	5		ENSP00000385708.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251304 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2024

The c.84G>C (p.E28D) alteration is located in exon 1 (coding exon 1) of the TTC32 gene. This alteration results from a G to C substitution at nucleotide position 84, causing the glutamic acid (E) at amino acid position 28 to be replaced by an aspartic acid (D). 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	Pathogenic	0.60
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.058	.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D;N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;T
Sift4G	Pathogenic	0.0	D;T
Polyphen		0.97	.;D
Vest4		0.34
MutPred		0.31		Gain of helix (P = 0.0861);Gain of helix (P = 0.0861);
MVP		0.86
MPC		0.20
ClinPred		0.71	D
GERP RS		1.4
Varity_R		0.14
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749247504; hg19: chr2-20101532; COSMIC: COSV61267794; COSMIC: COSV61267794;