chr6-167340367-A-T

Position:

• chr6-167340367-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_031949.5(TTLL2):​c.467A>T​(p.Lys156Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTLL2 NM_031949.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

Genes affected

TTLL2 (HGNC:21211): (tubulin tyrosine ligase like 2) Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule cytoskeleton organization and protein polyglutamylation. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL2	NM_031949.5	c.467A>T	p.Lys156Ile	missense_variant	3/3	ENST00000239587.10	NP_114155.4
TTLL2	NM_001410948.1	c.248A>T	p.Lys83Ile	missense_variant	2/2		NP_001397877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTLL2	ENST00000239587.10	c.467A>T	p.Lys156Ile	missense_variant	3/3	1	NM_031949.5	ENSP00000239587.5
TTLL2	ENST00000515138.1	n.467A>T		non_coding_transcript_exon_variant	3/6	1		ENSP00000424130.1
TTLL2	ENST00000649884.1	c.248A>T	p.Lys83Ile	missense_variant	2/2			ENSP00000497040.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 08, 2024

The c.467A>T (p.K156I) alteration is located in exon 3 (coding exon 3) of the TTLL2 gene. This alteration results from a A to T substitution at nucleotide position 467, causing the lysine (K) at amino acid position 156 to be replaced by an isoleucine (I). 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	0.99
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.69	T;.
M_CAP	Benign	0.0042	T
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	4.8	.;H
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-7.9	.;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	.;D
Polyphen		1.0	.;D
Vest4		0.59
MutPred		0.88		.;Loss of disorder (P = 0.0087);
MVP		0.092
MPC		0.75
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.98
gMVP		0.88

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: rs1355690250; hg19: chr6-167753855;