chr2-161424221-C-G

Variant names:

• chr2-161424221-C-G
• rs1310795066
• NM_006593.4:c.2043C>G
• TBR1 p.His681Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_006593.4(TBR1):c.2043C>G (p.His681Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000014 (AC=2) in the gnomAD database across 1,424,444 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000811. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.H681P: Uncertain_significance (ClinVar VariationId 1203893, 1 star)

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBR1 NM_006593.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.46
• Publications: 0 publications found

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]

TBR1 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with autism and speech delay

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• occipital pachygyria and polymicrogyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251621 (HGNC:):

SLC4A10 (HGNC:13811): (solute carrier family 4 member 10) This gene belongs to a small family of sodium-coupled bicarbonate transporters (NCBTs) that regulate the intracellular pH of neurons, the secretion of bicarbonate ions across the choroid plexus, and the pH of the brain extracellular fluid. The protein encoded by this gene was initially identified as a sodium-driven chloride bicarbonate exchanger (NCBE) though there is now evidence that its sodium/bicarbonate cotransport activity is independent of any chloride ion countertransport under physiological conditions. This gene is now classified as a member A10 of the SLC4 family of transmembrane solute carriers. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, May 2010]

SLC4A10 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: STRONG Submitted by: ClinGen
• neurodevelopmental disorder with hypotonia and characteristic brain abnormalities

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Baylor College of Medicine Research Center, G2P

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000811 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006593.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TBR1 NM_006593.4	MANE Select	c.2043C>G p.His681Gln	missense	Exon 6 of 6	Prot: NP_006584.1 UniProt:

TBR1 NM_006593.4

MANE Select

HGVSc / HGVSpc.2043C>Gp.His681Gln

Exon rankExon 6 of 6

missense

Prot: NP_006584.1UniProt: Q16650-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TBR1 ENST00000389554.8	TSL:1MANE Select	c.2043C>G p.His681Gln	missense	Exon 6 of 6	Prot: ENSP00000374205.3 UniProt:
	TBR1 ENST00000410035.1	TSL:2	c.1182C>G p.His394Gln	missense	Exon 5 of 5	Prot: ENSP00000387023.1 UniProt:
	ENSG00000251621 ENST00000505579.1	TSL:4	n.207C>G	non_coding_transcript_exon	Exon 1 of 2	Prot:

TBR1 ENST00000389554.8

TSL:1MANE Select

HGVSc / HGVSpc.2043C>Gp.His681Gln

Exon rankExon 6 of 6

missense

Prot: ENSP00000374205.3UniProt: Q16650-1

TBR1 ENST00000410035.1

TSL:2

HGVSc / HGVSpc.1182C>Gp.His394Gln

Exon rankExon 5 of 5

missense

Prot: ENSP00000387023.1UniProt: Q16650-2

ENSG00000251621 ENST00000505579.1

TSL:4

HGVSc / HGVSpn.207C>G

Exon rankExon 1 of 2

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00	AC:0	Hom:0	AN:151740	Cov:32
GnomAD2 exomes	AF: 0.00000504	AC:1	Hom:	AN:198378	Cov:
GnomAD4 exome	AF: 0.00000140	AC:2	Hom:0	AN:1424444	Cov:38
GnomAD4 genome Warning	AF: 0.00	AC:0	Hom:0	AN:151740	Cov:32
TOPMed (Bravo)	AF: 0.0000189	AC:5	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000742	AC:1	Hom:0	AN:13470	Cov:

Showing 6 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
FuncVEP CTI	Benign	0.0090
GPN-Star LLR	N/A	-8.8
GPN-Star score	N/A	8.8
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.11	D
Mutation Taster	N/A	24/76	disease causing
MutationAssessor	Uncertain	2.1	M
PhyloP100	Benign	2.5
popEVE	Benign	-3.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.032	D
Varity_R	N/A	0.24
VESM-3B	Benign	-5.8

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1310795066;

hg19: chr2-162280732;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar