rs200707564

Variant names:

• chr16-58523363-C-A
• rs200707564
• NM_001160305.4:c.*4334C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-58523363-C-A
• chr16-58523363-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016284.5(CNOT1):​c.6917+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CNOT1 NM_016284.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003343
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 0 publications found

Genes affected

SETD6 (HGNC:26116): (SET domain containing 6, protein lysine methyltransferase) This gene encodes a methyltransferase that adds a methyl group to the histone H2AZ, which is involved in nuclear receptor-dependent transcription. The protein also interacts with several endogenous proteins which are involved in nuclear hormone receptor signaling. A related pseudogene is located on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

CNOT1 (HGNC:7877): (CCR4-NOT transcription complex subunit 1) Enables armadillo repeat domain binding activity; molecular adaptor activity; and nuclear receptor binding activity. Contributes to poly(A)-specific ribonuclease activity. Involved in several processes, including negative regulation of signal transduction; positive regulation of cytoplasmic mRNA processing body assembly; and regulation of gene expression. Located in P-body and cytosol. Part of CCR4-NOT complex. Implicated in holoprosencephaly. [provided by Alliance of Genome Resources, Apr 2022]

CNOT1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• holoprosencephaly 12 with or without pancreatic agenesis

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Vissers-Bodmer syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000276259 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016284.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD6	NM_001160305.4	MANE Select	c.*4334C>A		3_prime_UTR	Exon 8 of 8	NP_001153777.1	Q8TBK2-1
	CNOT1	NM_016284.5	MANE Select	c.6917+7G>T		splice_region intron	N/A	NP_057368.3
	CNOT1	NM_001265612.2		c.6902+7G>T		splice_region intron	N/A	NP_001252541.1	A5YKK6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD6	ENST00000219315.9	TSL:1 MANE Select	c.*4334C>A		3_prime_UTR	Exon 8 of 8	ENSP00000219315.5	Q8TBK2-1
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.6917+7G>T		splice_region intron	N/A	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.6902+7G>T		splice_region intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414660 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 701978

African (AFR) AF: 0.00 AC: 0 AN: 31824

American (AMR) AF: 0.00 AC: 0 AN: 39238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24412

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39080

South Asian (SAS) AF: 0.00 AC: 0 AN: 77082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087772

Other (OTH) AF: 0.00 AC: 0 AN: 58010

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.73
PhyloP100		-0.078

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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: rs200707564; hg19: chr16-58557267;