rs2492367

Positions:

• chr1-231770843-C-G
• chr1-231770843-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018662.3(DISC1):​c.1407C>G​(p.Ile469Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19929779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISC1	NM_018662.3	c.1407C>G	p.Ile469Met	missense_variant	6/13	ENST00000439617.8
TSNAX-DISC1	NR_028393.1	n.2128C>G		non_coding_transcript_exon_variant	10/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISC1	ENST00000439617.8	c.1407C>G	p.Ile469Met	missense_variant	6/13	5	NM_018662.3	A2
	ENST00000651424.1	n.537-2481G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247762 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461580 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.018
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	.;.;.;.;.;.;.;.;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.1	.;L;L;L;.;L;L;L;L;L
MutationTaster	Benign	0.99	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	.;N;.;N;N;N;.;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.046	.;D;.;.;D;D;.;D;T;T
Sift4G	Uncertain	0.010	D;D;D;D;D;D;T;D;T;D
Polyphen		0.91, 0.78, 0.82, 0.68	.;.;.;.;P;P;.;.;P;P
Vest4		0.19
MutPred		0.42		.;Gain of ubiquitination at K467 (P = 0.0725);Gain of ubiquitination at K467 (P = 0.0725);Gain of ubiquitination at K467 (P = 0.0725);Gain of ubiquitination at K467 (P = 0.0725);Gain of ubiquitination at K467 (P = 0.0725);Gain of ubiquitination at K467 (P = 0.0725);Gain of ubiquitination at K467 (P = 0.0725);Gain of ubiquitination at K467 (P = 0.0725);Gain of ubiquitination at K467 (P = 0.0725);
MVP		0.73
MPC		0.27
ClinPred		0.56	D
GERP RS		-6.0
Varity_R		0.038
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2492367; hg19: chr1-231906589;