chr2-216100396-A-G

Variant summary

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

The ENST00000437356.7(TMEM169):ā€‹c.748A>Gā€‹(p.Lys250Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

TMEM169
ENST00000437356.7 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.29
Variant links:
Genes affected
TMEM169 (HGNC:25130): (transmembrane protein 169) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM169NM_001142311.2 linkuse as main transcriptc.748A>G p.Lys250Glu missense_variant 3/3 ENST00000437356.7 NP_001135783.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM169ENST00000437356.7 linkuse as main transcriptc.748A>G p.Lys250Glu missense_variant 3/31 NM_001142311.2 ENSP00000401305 P1
TMEM169ENST00000406027.2 linkuse as main transcriptc.748A>G p.Lys250Glu missense_variant 3/31 ENSP00000384100 P1
TMEM169ENST00000295658.8 linkuse as main transcriptc.748A>G p.Lys250Glu missense_variant 3/32 ENSP00000295658 P1
TMEM169ENST00000454545.5 linkuse as main transcriptc.748A>G p.Lys250Glu missense_variant 4/44 ENSP00000412524 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2023The c.748A>G (p.K250E) 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 748, causing the lysine (K) at amino acid position 250 to be replaced by a glutamic acid (E). 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
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.45
T;T;T;T
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D;.;.;.
M_CAP
Benign
0.015
T
MetaRNN
Uncertain
0.68
D;D;D;D
MetaSVM
Benign
-0.76
T
MutationAssessor
Uncertain
2.8
M;M;M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-4.0
D;D;D;D
REVEL
Uncertain
0.41
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
0.096
B;B;B;B
Vest4
0.90
MutPred
0.64
Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);
MVP
0.28
MPC
0.68
ClinPred
0.99
D
GERP RS
3.9
Varity_R
0.86
gMVP
0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1696369048; hg19: chr2-216965119; API