6-167341487-G-T

Variant names:

• chr6-167341487-G-T
• rs12528714
• NM_031949.5:c.1587G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031949.5(TTLL2):​c.1587G>T​(p.Gln529His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,614,076 control chromosomes in the GnomAD database, including 1,329 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.027 (122 hom., cov: 31)
  • Exomes 𝑓: 0.028 (1207 hom.)
• Consequence: TTLL2 NM_031949.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.602
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017136633).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0961 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031949.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL2	NM_031949.5	MANE Select	c.1587G>T	p.Gln529His	missense	Exon 3 of 3	NP_114155.4
	TTLL2	NM_001410948.1		c.1368G>T	p.Gln456His	missense	Exon 2 of 2	NP_001397877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL2	ENST00000239587.10	TSL:1 MANE Select	c.1587G>T	p.Gln529His	missense	Exon 3 of 3	ENSP00000239587.5
	TTLL2	ENST00000515138.1	TSL:1	n.1587G>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000424130.1
	TTLL2	ENST00000649884.1		c.1368G>T	p.Gln456His	missense	Exon 2 of 2	ENSP00000497040.1

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4165 AN: 152072 Hom.: 119 Cov.: 31

Gnomad AFR AF: 0.00998

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.0592

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0427 AC: 10749 AN: 251470 AF XY: 0.0377

Gnomad AFR exome AF: 0.00787

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.0503

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0336

GnomAD4 exome AF: 0.0280 AC: 40984 AN: 1461886 Hom.: 1207 Cov.: 33 AF XY: 0.0271 AC XY: 19685 AN XY: 727246

African (AFR) AF: 0.00717 AC: 240 AN: 33478

American (AMR) AF: 0.162 AC: 7248 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 398 AN: 26136

East Asian (EAS) AF: 0.0700 AC: 2778 AN: 39700

South Asian (SAS) AF: 0.0221 AC: 1904 AN: 86258

European-Finnish (FIN) AF: 0.0300 AC: 1603 AN: 53420

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.0225 AC: 25046 AN: 1112006

Other (OTH) AF: 0.0286 AC: 1726 AN: 60396

GnomAD4 genome AF: 0.0274 AC: 4175 AN: 152190 Hom.: 122 Cov.: 31 AF XY: 0.0293 AC XY: 2178 AN XY: 74412

African (AFR) AF: 0.00995 AC: 413 AN: 41518

American (AMR) AF: 0.100 AC: 1534 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3464

East Asian (EAS) AF: 0.0596 AC: 307 AN: 5154

South Asian (SAS) AF: 0.0235 AC: 113 AN: 4818

European-Finnish (FIN) AF: 0.0305 AC: 323 AN: 10600

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0197 AC: 1342 AN: 68018

Other (OTH) AF: 0.0422 AC: 89 AN: 2110

Alfa AF: 0.0246 Hom.: 199

Bravo AF: 0.0342

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0194 AC: 167

ExAC AF: 0.0366 AC: 4443

Asia WGS AF: 0.0610 AC: 213 AN: 3478

EpiCase AF: 0.0173

EpiControl AF: 0.0168

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.60
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.022
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.021	D
Polyphen		0.98	D
Vest4		0.039
MutPred		0.25		Gain of catalytic residue at Q529 (P = 0.0214)
MPC		0.44
ClinPred		0.021	T
GERP RS		0.78
Varity_R		0.11
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12528714; hg19: chr6-167754975; COSMIC: COSV53442971; COSMIC: COSV53442971;