rs2412646

Variant names:

• chr4-55452605-T-C
• rs2412646
• NM_004898.4:c.1206+449A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.1206+449A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 172,352 control chromosomes in the GnomAD database, including 31,980 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (27591 hom., cov: 32)
  • Exomes 𝑓: 0.65 (4389 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• Publications: 13 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 glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.1206+449A>G		intron_variant	Intron 15 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.1206+449A>G		intron_variant	Intron 15 of 22	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88835 AN: 151890 Hom.: 27570 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.809

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.582

GnomAD4 exome AF: 0.647 AC: 13170 AN: 20342 Hom.: 4389 Cov.: 0 AF XY: 0.654 AC XY: 7443 AN XY: 11378

African (AFR) AF: 0.333 AC: 44 AN: 132

American (AMR) AF: 0.688 AC: 1640 AN: 2382

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 96 AN: 162

East Asian (EAS) AF: 0.694 AC: 762 AN: 1098

South Asian (SAS) AF: 0.787 AC: 2086 AN: 2652

European-Finnish (FIN) AF: 0.686 AC: 387 AN: 564

Middle Eastern (MID) AF: 0.375 AC: 9 AN: 24

European-Non Finnish (NFE) AF: 0.612 AC: 7633 AN: 12466

Other (OTH) AF: 0.595 AC: 513 AN: 862

GnomAD4 genome AF: 0.585 AC: 88870 AN: 152010 Hom.: 27591 Cov.: 32 AF XY: 0.597 AC XY: 44381 AN XY: 74316

African (AFR) AF: 0.370 AC: 15338 AN: 41434

American (AMR) AF: 0.672 AC: 10264 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2271 AN: 3470

East Asian (EAS) AF: 0.684 AC: 3530 AN: 5162

South Asian (SAS) AF: 0.810 AC: 3909 AN: 4824

European-Finnish (FIN) AF: 0.752 AC: 7946 AN: 10572

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.643 AC: 43689 AN: 67978

Other (OTH) AF: 0.586 AC: 1237 AN: 2110

Alfa AF: 0.609 Hom.: 3803

Bravo AF: 0.563

Asia WGS AF: 0.736 AC: 2560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.16
DANN	Benign	0.45
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2412646; hg19: chr4-56318772;