NM_001164407.2:c.277G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001164407.2(TLCD2):​c.277G>A​(p.Gly93Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000433 in 1,384,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

TLCD2
NM_001164407.2 missense

Scores

2
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78
Variant links:
Genes affected
TLCD2 (HGNC:33522): (TLC domain containing 2) Involved in several processes, including membrane assembly; phospholipid homeostasis; and regulation of membrane lipid distribution. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TLCD2NM_001164407.2 linkc.277G>A p.Gly93Arg missense_variant Exon 3 of 4 ENST00000330676.8 NP_001157879.1 A6NGC4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TLCD2ENST00000330676.8 linkc.277G>A p.Gly93Arg missense_variant Exon 3 of 4 2 NM_001164407.2 ENSP00000331965.6 A6NGC4

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD3 exomes
AF:
0.00000693
AC:
1
AN:
144292
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
77074
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000941
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000433
AC:
6
AN:
1384914
Hom.:
0
Cov.:
33
AF XY:
0.00000293
AC XY:
2
AN XY:
683384
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000840
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.27e-7
Gnomad4 OTH exome
AF:
0.0000345
GnomAD4 genome
Cov.:
30
Bravo
AF:
0.0000113

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.277G>A (p.G93R) alteration is located in exon 3 (coding exon 3) of the TLCD2 gene. This alteration results from a G to A substitution at nucleotide position 277, causing the glycine (G) at amino acid position 93 to be replaced by an arginine (R). 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
0.78
BayesDel_addAF
Uncertain
0.074
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.40
T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.53
D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Benign
-0.47
T
MutationAssessor
Uncertain
2.2
M
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.6
N
REVEL
Uncertain
0.60
Sift
Benign
0.084
T
Sift4G
Benign
0.16
T
Vest4
0.70
MutPred
0.82
Gain of helix (P = 0.132);
MVP
0.52
ClinPred
0.22
T
GERP RS
2.2
Varity_R
0.074
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1423330679; hg19: chr17-1612858; API