rs767536605

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-44146858-C-A
• chr6-44146858-C-G
• chr6-44146858-C-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>A​(p.Pro265His) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P265L) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: TMEM63B NM_018426.3 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.38303795).

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>A	p.Pro265His	missense	Exon 11 of 24	NP_060896.1	Q5T3F8-1
	TMEM63B	NM_001318792.1		c.794C>A	p.Pro265His	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>A	p.Pro265His	missense	Exon 11 of 24	ENSP00000327154.6	Q5T3F8-1
	TMEM63B	ENST00000371893.6	TSL:1	c.578C>A	p.Pro193His	missense	Exon 8 of 21	ENSP00000360960.2	H3BLW6
	TMEM63B	ENST00000533121.1	TSL:1	n.239C>A		non_coding_transcript_exon	Exon 4 of 16	ENSP00000432085.1	H0YCP6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251468 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.0000724 AC: 3 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.97	D
Vest4		0.39
MutPred		0.67		Gain of phosphorylation at Y264 (P = 0.0909)
MVP		0.13
MPC		1.6
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.77
Mutation Taster		=88/12	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;