chr2-134713295-A-G

Position:

• chr2-134713295-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PM5 PP3 PP5_Moderate

The NM_030923.5(TMEM163):​c.227T>C​(p.Leu76Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L76R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM163 NM_030923.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.80

Genes affected

TMEM163 (HGNC:25380): (transmembrane protein 163) Predicted to enable zinc ion binding activity. Predicted to be involved in zinc ion import into synaptic vesicle. Predicted to be located in early endosome membrane. Predicted to be active in intracellular vesicle and plasma membrane. Predicted to be integral component of synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_030923.5 (TMEM163) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a topological_domain Cytoplasmic (size 87) in uniprot entity TM163_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_030923.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-134713295-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2443750.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815
• PP5: Variant 2-134713295-A-G is Pathogenic according to our data. Variant chr2-134713295-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2443749.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM163	NM_030923.5	c.227T>C	p.Leu76Pro	missense_variant	2/8	ENST00000281924.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM163	ENST00000281924.6	c.227T>C	p.Leu76Pro	missense_variant	2/8	1	NM_030923.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leukodystrophy, hypomyelinating, 25 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Nov 07, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.047	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.46		Gain of relative solvent accessibility (P = 0.0027);
MVP		0.17
MPC		2.0
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.44
gMVP		0.74

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-135470865;