4-55435441-C-G
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_004898.4(CLOCK):c.2515G>C(p.Asp839His) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CLOCK
NM_004898.4 missense
NM_004898.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 6.47
Publications
0 publications found
Genes affected
CLOCK (HGNC:2082): (clock circadian regulator) The protein encoded by this gene plays a central role in the regulation of circadian rhythms. The protein encodes a transcription factor of the basic helix-loop-helix (bHLH) family and contains DNA binding histone acetyltransferase activity. The encoded protein forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Polymorphisms in this gene may be associated with behavioral changes in certain populations and with obesity and metabolic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
TMEM165 (HGNC:30760): (transmembrane protein 165) This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene's expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]
TMEM165 Gene-Disease associations (from GenCC):
- TMEM165-congenital disorder of glycosylationInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152152
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461674Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727154 show subpopulations
GnomAD4 exome
AF:
AC:
4
AN:
1461674
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727154
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33464
American (AMR)
AF:
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26128
East Asian (EAS)
AF:
AC:
0
AN:
39690
South Asian (SAS)
AF:
AC:
0
AN:
86244
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
3
AN:
1111870
Other (OTH)
AF:
AC:
1
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152152
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74332
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41422
American (AMR)
AF:
AC:
0
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3468
East Asian (EAS)
AF:
AC:
0
AN:
5190
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68032
Other (OTH)
AF:
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Dec 20, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.2515G>C (p.D839H) alteration is located in exon 23 (coding exon 20) of the CLOCK gene. This alteration results from a G to C substitution at nucleotide position 2515, causing the aspartic acid (D) at amino acid position 839 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0397);Gain of MoRF binding (P = 0.0397);Gain of MoRF binding (P = 0.0397);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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