chr2-216096014-C-A

Position:

• chr2-216096014-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142311.2(TMEM169):​c.51C>A​(p.His17Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM169 NM_001142311.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.818

Genes affected

TMEM169 (HGNC:25130): (transmembrane protein 169) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026423752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM169	NM_001142311.2	c.51C>A	p.His17Gln	missense_variant	2/3	ENST00000437356.7	NP_001135783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM169	ENST00000437356.7	c.51C>A	p.His17Gln	missense_variant	2/3	1	NM_001142311.2	ENSP00000401305	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.51C>A (p.H17Q) alteration is located in exon 3 (coding exon 1) of the TMEM169 gene. This alteration results from a C to A substitution at nucleotide position 51, causing the histidine (H) at amino acid position 17 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.7
DANN	Benign	0.70
DEOGEN2	Benign	0.0061	T;T;T;T;T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.43	T;T;.;.;T;.
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.026	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.58	N;N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.43	T;T;T;T;T;T
Sift4G	Benign	0.62	T;T;T;T;T;T
Polyphen		0.0010	.;B;B;B;.;B
Vest4		0.13, 0.10
MutPred		0.12		Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);
MVP		0.014
MPC		0.12
ClinPred		0.077	T
GERP RS		-0.23
Varity_R		0.062
gMVP		0.049

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: chr2-216960737;