rs6811520

Variant names:

• chr4-55449011-T-C
• rs6811520
• NM_004898.4:c.1450-143A>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.1450-143A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 683,606 control chromosomes in the GnomAD database, including 164,981 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 0.72 (39732 hom., cov: 31)
  • Exomes 𝑓: 0.68 (125249 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180
• Publications: 26 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.1450-143A>G		intron_variant	Intron 17 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.1450-143A>G		intron_variant	Intron 17 of 22	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.717 AC: 108955 AN: 151854 Hom.: 39661 Cov.: 31

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.682 AC: 362644 AN: 531632 Hom.: 125249 AF XY: 0.687 AC XY: 194492 AN XY: 283134

African (AFR) AF: 0.834 AC: 12040 AN: 14434

American (AMR) AF: 0.736 AC: 18655 AN: 25340

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 10683 AN: 16028

East Asian (EAS) AF: 0.747 AC: 23399 AN: 31330

South Asian (SAS) AF: 0.806 AC: 41155 AN: 51046

European-Finnish (FIN) AF: 0.737 AC: 24299 AN: 32948

Middle Eastern (MID) AF: 0.627 AC: 1677 AN: 2674

European-Non Finnish (NFE) AF: 0.642 AC: 211104 AN: 328860

Other (OTH) AF: 0.678 AC: 19632 AN: 28972

GnomAD4 genome AF: 0.718 AC: 109083 AN: 151974 Hom.: 39732 Cov.: 31 AF XY: 0.725 AC XY: 53806 AN XY: 74256

African (AFR) AF: 0.833 AC: 34568 AN: 41490

American (AMR) AF: 0.720 AC: 10997 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2274 AN: 3470

East Asian (EAS) AF: 0.684 AC: 3511 AN: 5136

South Asian (SAS) AF: 0.814 AC: 3922 AN: 4820

European-Finnish (FIN) AF: 0.750 AC: 7907 AN: 10536

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.644 AC: 43760 AN: 67942

Other (OTH) AF: 0.684 AC: 1444 AN: 2110

Alfa AF: 0.672 Hom.: 17672

Bravo AF: 0.715

Asia WGS AF: 0.769 AC: 2676 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.0
DANN	Benign	0.44
PhyloP100		0.018
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: rs6811520; hg19: chr4-56315178; COSMIC: COSV59400764; COSMIC: COSV59400764;