chr6-44146858-C-T

Variant names:

• chr6-44146858-C-T
• rs767536605
• NM_018426.3:c.794C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_018426.3(TMEM63B):​c.794C>T​(p.Pro265Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM63B NM_018426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86
• Publications: 0 publications found

Genes affected

TMEM63B (HGNC:17735): (transmembrane protein 63B) Predicted to enable calcium activated cation channel activity; mechanosensitive ion channel activity; and osmolarity-sensing cation channel activity. Predicted to be involved in cation transmembrane transport. Located in actin cytoskeleton and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM63B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• TMEM63B-related developmental and epileptic encephalopathy with anemia

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.2176 (above the threshold of 3.09). Trascript score misZ: 5.4805 (above the threshold of 3.09). GenCC associations: The gene is linked to TMEM63B-related developmental and epileptic encephalopathy with anemia, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3720423).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018426.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM63B	NM_018426.3	MANE Select	c.794C>T	p.Pro265Leu	missense	Exon 11 of 24	NP_060896.1	Q5T3F8-1
	TMEM63B	NM_001318792.1		c.794C>T	p.Pro265Leu	missense	Exon 11 of 24	NP_001305721.1	Q5T3F8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM63B	ENST00000323267.11	TSL:5 MANE Select	c.794C>T	p.Pro265Leu	missense	Exon 11 of 24	ENSP00000327154.6	Q5T3F8-1
	TMEM63B	ENST00000371893.6	TSL:1	c.578C>T	p.Pro193Leu	missense	Exon 8 of 21	ENSP00000360960.2	H3BLW6
	TMEM63B	ENST00000533121.1	TSL:1	n.239C>T		non_coding_transcript_exon	Exon 4 of 16	ENSP00000432085.1	H0YCP6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.70	P
Vest4		0.35
MutPred		0.67		Loss of helix (P = 0.0558)
MVP		0.17
MPC		1.2
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.79
Mutation Taster		=89/11	polymorphism

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: rs767536605; hg19: chr6-44114595;