NM_004898.4:c.1131-54G>C

Variant names:

• chr4-55453183-C-G
• rs11240
• NM_004898.4:c.1131-54G>C

Variant summary

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

The NM_004898.4(CLOCK):​c.1131-54G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,355,770 control chromosomes in the GnomAD database, including 51,640 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 0.25 (4946 hom., cov: 32)
  • Exomes 𝑓: 0.27 (46694 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0880
• Publications: 17 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=-0.75).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.1131-54G>C		intron_variant	Intron 14 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.1131-54G>C		intron_variant	Intron 14 of 22	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.1131-54G>C		intron_variant	Intron 13 of 21	1		ENSP00000308741.4
CLOCK	ENST00000381322.5	c.1131-54G>C		intron_variant	Intron 15 of 23	1		ENSP00000370723.1
TMEM165	ENST00000608091.1	c.*877C>G		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000476531.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37431 AN: 151962 Hom.: 4940 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.0989

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.247

GnomAD4 exome AF: 0.274 AC: 329895 AN: 1203690 Hom.: 46694 Cov.: 16 AF XY: 0.278 AC XY: 170300 AN XY: 611904

African (AFR) AF: 0.176 AC: 4951 AN: 28180

American (AMR) AF: 0.218 AC: 9639 AN: 44132

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 5714 AN: 24490

East Asian (EAS) AF: 0.127 AC: 4854 AN: 38094

South Asian (SAS) AF: 0.362 AC: 29323 AN: 80924

European-Finnish (FIN) AF: 0.342 AC: 18097 AN: 52934

Middle Eastern (MID) AF: 0.268 AC: 1409 AN: 5264

European-Non Finnish (NFE) AF: 0.276 AC: 242295 AN: 878100

Other (OTH) AF: 0.264 AC: 13613 AN: 51572

GnomAD4 genome AF: 0.246 AC: 37456 AN: 152080 Hom.: 4946 Cov.: 32 AF XY: 0.251 AC XY: 18685 AN XY: 74336

African (AFR) AF: 0.172 AC: 7130 AN: 41500

American (AMR) AF: 0.233 AC: 3565 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 819 AN: 3468

East Asian (EAS) AF: 0.0988 AC: 511 AN: 5174

South Asian (SAS) AF: 0.372 AC: 1795 AN: 4826

European-Finnish (FIN) AF: 0.357 AC: 3766 AN: 10554

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19032 AN: 67960

Other (OTH) AF: 0.245 AC: 517 AN: 2110

Alfa AF: 0.131 Hom.: 289

Bravo AF: 0.226

Asia WGS AF: 0.260 AC: 905 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.9
DANN	Benign	0.59
PhyloP100		-0.088
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs11240; hg19: chr4-56319350; COSMIC: COSV107379064; COSMIC: COSV107379064;