2-74490305-G-C

Variant names:

• chr2-74490305-G-C
• rs1673692148
• NM_022492.6:c.294G>C

Variant summary

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

The NM_022492.6(TTC31):​c.294G>C​(p.Lys98Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,864 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TTC31 NM_022492.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0610

Genes affected

TTC31 (HGNC:25759): (tetratricopeptide repeat domain 31)

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=0.15525866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC31	NM_022492.6	c.294G>C	p.Lys98Asn	missense_variant	Exon 4 of 13	ENST00000233623.11	NP_071937.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC31	ENST00000233623.11	c.294G>C	p.Lys98Asn	missense_variant	Exon 4 of 13	1	NM_022492.6	ENSP00000233623.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.294G>C (p.K98N) alteration is located in exon 4 (coding exon 4) of the TTC31 gene. This alteration results from a G to C substitution at nucleotide position 294, causing the lysine (K) at amino acid position 98 to be replaced by an asparagine (N). 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	Benign	0.27
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0096	.;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L;.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	.;N;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.84	.;.;P
Vest4		0.16
MutPred		0.17		Loss of ubiquitination at K98 (P = 0.0034);Loss of ubiquitination at K98 (P = 0.0034);Loss of ubiquitination at K98 (P = 0.0034);
MVP		0.61
MPC		0.39
ClinPred		0.57	D
GERP RS		-0.89
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.18
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1673692148; hg19: chr2-74717432;