1-231694549-G-C

Variant names:

• chr1-231694549-G-C
• rs3738401
• NM_018662.3:c.791G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018662.3(DISC1):​c.791G>C​(p.Arg264Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033829987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.791G>C	p.Arg264Pro	missense_variant	Exon 2 of 13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.791G>C	p.Arg264Pro	missense_variant	Exon 2 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.791G>C	p.Arg264Pro	missense_variant	Exon 2 of 13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.*652G>C		non_coding_transcript_exon_variant	Exon 6 of 13	2		ENSP00000473532.1
TSNAX-DISC1	ENST00000602956.5	n.*652G>C		3_prime_UTR_variant	Exon 6 of 13	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461728 Hom.: 0 Cov.: 92 AF XY: 0.0000110 AC XY: 8 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.048
DANN	Benign	0.74
DEOGEN2	Benign	0.0085	.;.;.;.;.;.;.;.;.;T;.;T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.59	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;N;N;N;.;N;N;N;N;.;.;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.85	N;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.033
Sift	Benign	0.17	T;T;.;.;T;T;.;T;T;.;.;T;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;.;.;.;B;B;.;.;B;.;.;B;.
Vest4		0.075
MutPred		0.21		Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);Loss of MoRF binding (P = 0.0072);
MVP		0.088
MPC		0.16
ClinPred		0.086	T
GERP RS		-9.9
Varity_R		0.11
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3738401; hg19: chr1-231830295;