2-161416586-T-C

Position:

• chr2-161416586-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006593.4(TBR1):​c.176T>C​(p.Met59Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBR1 NM_006593.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

Genes affected

TBR1 (HGNC:11590): (T-box brain transcription factor 1) This gene is a member of a conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBR1	NM_006593.4	c.176T>C	p.Met59Thr	missense_variant	1/6	ENST00000389554.8	NP_006584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBR1	ENST00000389554.8	c.176T>C	p.Met59Thr	missense_variant	1/6	1	NM_006593.4	ENSP00000374205.3
TBR1	ENST00000463544.1	n.256T>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.096	T
Polyphen		0.93	P
Vest4		0.87
MutPred		0.29		Gain of glycosylation at M59 (P = 0.0099);
MVP		0.65
ClinPred		0.83	D
GERP RS		5.2
Varity_R		0.59
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-162273097;