1-231626909-C-A

Variant names:

• chr1-231626909-C-A
• rs566458514
• NM_018662.3:c.42C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_018662.3(DISC1):​c.42C>A​(p.Gly14Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000296 in 1,350,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G14G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: DISC1 NM_018662.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.715
• Publications: 0 publications found

Genes affected

DISC1 (HGNC:2888): (DISC1 scaffold protein) This gene encodes a protein with multiple coiled coil motifs which is located in the nucleus, cytoplasm and mitochondria. The protein is involved in neurite outgrowth and cortical development through its interaction with other proteins. This gene is disrupted in a t(1;11)(q42.1;q14.3) translocation which segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

TSNAX-DISC1 (HGNC:49177): (TSNAX-DISC1 readthrough (NMD candidate)) This gene represents naturally occurring read-through transcription between the neighboring TSNAX (translin-associated factor X) and DISC1 (disrupted in schizophrenia 1) genes on chromosome 1. Alternative splicing results in multiple transcript variants, all of which are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to be protein-coding. These alterations in gene processing may be associated with risk for psychiatric illness, most notably, schizophrenia. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP7: Synonymous conserved (PhyloP=-0.715 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018662.3. 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
	DISC1	NM_018662.3	MANE Select	c.42C>A	p.Gly14Gly	synonymous	Exon 1 of 13	NP_061132.2	Q9NRI5-1
	DISC1	NM_001164537.2		c.42C>A	p.Gly14Gly	synonymous	Exon 1 of 14	NP_001158009.1	C4P096
	DISC1	NM_001012957.2		c.42C>A	p.Gly14Gly	synonymous	Exon 1 of 13	NP_001012975.1	Q9NRI5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	ENST00000439617.8	TSL:5 MANE Select	c.42C>A	p.Gly14Gly	synonymous	Exon 1 of 13	ENSP00000403888.4	Q9NRI5-1
	DISC1	ENST00000366637.8	TSL:5	c.42C>A	p.Gly14Gly	synonymous	Exon 1 of 13	ENSP00000355597.6	Q9NRI5-2
	DISC1	ENST00000366633.7	TSL:1	c.42C>A	p.Gly14Gly	synonymous	Exon 1 of 10	ENSP00000355593.3	Q9NRI5-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000296 AC: 4 AN: 1350534 Hom.: 0 Cov.: 30 AF XY: 0.00000300 AC XY: 2 AN XY: 666578

African (AFR) AF: 0.00 AC: 0 AN: 27474

American (AMR) AF: 0.00 AC: 0 AN: 30400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23896

East Asian (EAS) AF: 0.00 AC: 0 AN: 32872

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4224

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1066026

Other (OTH) AF: 0.00 AC: 0 AN: 56154

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.8
DANN	Benign	0.81
PhyloP100		-0.71
PromoterAI		-0.0034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Mutation Taster		=299/1	polymorphism

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: rs566458514; hg19: chr1-231762655;