2-216100390-A-G

Position:

• chr2-216100390-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142311.2(TMEM169):​c.742A>G​(p.Met248Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 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: 5.06

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19032383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM169	NM_001142311.2	c.742A>G	p.Met248Val	missense_variant	3/3	ENST00000437356.7	NP_001135783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM169	ENST00000437356.7	c.742A>G	p.Met248Val	missense_variant	3/3	1	NM_001142311.2	ENSP00000401305.2
TMEM169	ENST00000406027.2	c.742A>G	p.Met248Val	missense_variant	3/3	1		ENSP00000384100.2
TMEM169	ENST00000295658.8	c.742A>G	p.Met248Val	missense_variant	3/3	2		ENSP00000295658.4
TMEM169	ENST00000454545.5	c.742A>G	p.Met248Val	missense_variant	4/4	4		ENSP00000412524.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 20, 2021

The c.742A>G (p.M248V) alteration is located in exon 4 (coding exon 2) of the TMEM169 gene. This alteration results from a A to G substitution at nucleotide position 742, causing the methionine (M) at amino acid position 248 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T;T;T;T
Eigen	Benign	0.092
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;.;.
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.4	L;L;L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.97	N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.27	B;B;B;B
Vest4		0.43
MutPred		0.25		Loss of ubiquitination at K250 (P = 0.0702);Loss of ubiquitination at K250 (P = 0.0702);Loss of ubiquitination at K250 (P = 0.0702);Loss of ubiquitination at K250 (P = 0.0702);
MVP		0.14
MPC		0.20
ClinPred		0.65	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.62

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: chr2-216965113;