NM_001017970.3:c.836C>T

Variant names:

• chr14-61280312-G-A
• NM_001017970.3:c.836C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001017970.3(TMEM30B):​c.836C>T​(p.Pro279Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM30B NM_001017970.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 9.00
• Publications: 0 publications found

Genes affected

TMEM30B (HGNC:27254): (transmembrane protein 30B) Enables aminophospholipid flippase activity. Involved in aminophospholipid transport and positive regulation of protein exit from endoplasmic reticulum. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus; endoplasmic reticulum; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

PRKCH (HGNC:9403): (protein kinase C eta) Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipids-dependent protein kinase. It is predominantly expressed in epithelial tissues and has been shown to reside specifically in the cell nucleus. This protein kinase can regulate keratinocyte differentiation by activating the MAP kinase MAPK13 (p38delta)-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha (CEBPA). It is also found to mediate the transcription activation of the transglutaminase 1 (TGM1) gene. Mutations in this gene are associated with susceptibility to cerebral infarction. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 14-61280312-G-A is Benign according to our data. Variant chr14-61280312-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2681613.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM30B	NM_001017970.3	c.836C>T	p.Pro279Leu	missense_variant	Exon 1 of 1	ENST00000555868.2	NP_001017970.1
PRKCH	XM_024449661.2	c.-121+92644G>A		intron_variant	Intron 1 of 13		XP_024305429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM30B	ENST00000555868.2	c.836C>T	p.Pro279Leu	missense_variant	Exon 1 of 1	6	NM_001017970.3	ENSP00000450842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461538 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

EBV-positive nodal T- and NK-cell lymphoma Benign:1

-

Department of Clinical Pathology, School of Medicine, Fujita Health University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.35
Sift	Benign	0.030	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.56		Loss of disorder (P = 0.0437);
MVP		0.24
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.56
gMVP		0.72
Mutation Taster		=64/36	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

hg19: chr14-61747030;