14-77255805-C-T

Variant names:

• chr14-77255805-C-T
• rs888059
• NM_020431.4:c.2221-721C>T

Variant summary

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

The NM_020431.4(TMEM63C):​c.2221-721C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 152,138 control chromosomes in the GnomAD database, including 15,909 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (15909 hom., cov: 33)
• Consequence: TMEM63C NM_020431.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.505
• Publications: 4 publications found

Genes affected

TMEM63C (HGNC:23787): (transmembrane protein 63C) Enables calcium activated cation channel activity. Involved in cation transport. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. Biomarker of focal segmental glomerulosclerosis. [provided by Alliance of Genome Resources, Apr 2022]

TMEM63C Gene-Disease associations (from GenCC):

• spastic paraplegia 87, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020431.4. 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
	TMEM63C	NM_020431.4	MANE Select	c.2221-721C>T		intron	N/A	NP_065164.2	Q9P1W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM63C	ENST00000298351.5	TSL:1 MANE Select	c.2221-721C>T		intron	N/A	ENSP00000298351.4	Q9P1W3
	TMEM63C	ENST00000890516.1		c.2221-718C>T		intron	N/A	ENSP00000560575.1
	TMEM63C	ENST00000890513.1		c.2221-721C>T		intron	N/A	ENSP00000560572.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64261 AN: 152020 Hom.: 15851 Cov.: 33

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.418

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.423 AC: 64379 AN: 152138 Hom.: 15909 Cov.: 33 AF XY: 0.425 AC XY: 31632 AN XY: 74376

African (AFR) AF: 0.659 AC: 27355 AN: 41492

American (AMR) AF: 0.467 AC: 7137 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1319 AN: 3470

East Asian (EAS) AF: 0.658 AC: 3412 AN: 5186

South Asian (SAS) AF: 0.394 AC: 1900 AN: 4822

European-Finnish (FIN) AF: 0.258 AC: 2730 AN: 10576

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19246 AN: 67980

Other (OTH) AF: 0.424 AC: 896 AN: 2114

Alfa AF: 0.400 Hom.: 2725

Bravo AF: 0.449

Asia WGS AF: 0.512 AC: 1782 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.35
PhyloP100		-0.51
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: rs888059; hg19: chr14-77722148;