rs6442905

Variant names:

• chr3-4775373-T-C
• rs6442905
• NM_001378452.1:c.6111T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):​c.6111T>C​(p.Asn2037Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,613,740 control chromosomes in the GnomAD database, including 761,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71220 hom., cov: 32)
  • Exomes 𝑓: 0.97 (689891 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.09
• Publications: 21 publications found

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ITPR1 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-4775373-T-C is Benign according to our data. Variant chr3-4775373-T-C is described in ClinVar as Benign. ClinVar VariationId is 1170008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. 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
	ITPR1	NM_001378452.1	MANE Select	c.6111T>C	p.Asn2037Asn	synonymous	Exon 47 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.6066T>C	p.Asn2022Asn	synonymous	Exon 46 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.5967T>C	p.Asn1989Asn	synonymous	Exon 44 of 59	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.6111T>C	p.Asn2037Asn	synonymous	Exon 47 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.6087T>C	p.Asn2029Asn	synonymous	Exon 47 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.6084T>C	p.Asn2028Asn	synonymous	Exon 47 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.967 AC: 147172 AN: 152216 Hom.: 71164 Cov.: 32

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.966

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.992

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.972

Gnomad OTH AF: 0.959

GnomAD2 exomes AF: 0.971 AC: 242087 AN: 249286 AF XY: 0.970

Gnomad AFR exome AF: 0.954

Gnomad AMR exome AF: 0.977

Gnomad ASJ exome AF: 0.954

Gnomad EAS exome AF: 0.987

Gnomad FIN exome AF: 0.992

Gnomad NFE exome AF: 0.970

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.972 AC: 1419914 AN: 1461406 Hom.: 689891 Cov.: 44 AF XY: 0.971 AC XY: 706047 AN XY: 727034

African (AFR) AF: 0.954 AC: 31921 AN: 33476

American (AMR) AF: 0.975 AC: 43611 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 24922 AN: 26136

East Asian (EAS) AF: 0.989 AC: 39258 AN: 39696

South Asian (SAS) AF: 0.960 AC: 82784 AN: 86254

European-Finnish (FIN) AF: 0.991 AC: 52921 AN: 53404

Middle Eastern (MID) AF: 0.968 AC: 5586 AN: 5768

European-Non Finnish (NFE) AF: 0.972 AC: 1080470 AN: 1111588

Other (OTH) AF: 0.968 AC: 58441 AN: 60360

GnomAD4 genome AF: 0.967 AC: 147287 AN: 152334 Hom.: 71220 Cov.: 32 AF XY: 0.967 AC XY: 72066 AN XY: 74490

African (AFR) AF: 0.954 AC: 39643 AN: 41572

American (AMR) AF: 0.966 AC: 14785 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 3299 AN: 3472

East Asian (EAS) AF: 0.985 AC: 5114 AN: 5192

South Asian (SAS) AF: 0.956 AC: 4603 AN: 4816

European-Finnish (FIN) AF: 0.992 AC: 10538 AN: 10618

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.972 AC: 66106 AN: 68040

Other (OTH) AF: 0.960 AC: 2029 AN: 2114

Alfa AF: 0.968 Hom.: 61129

Bravo AF: 0.964

Asia WGS AF: 0.966 AC: 3360 AN: 3478

EpiCase AF: 0.965

EpiControl AF: 0.967

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Gillespie syndrome (1)
-	-	1	Spinocerebellar ataxia type 15/16 (1)
-	-	1	Spinocerebellar ataxia type 29 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.15
DANN	Benign	0.26
PhyloP100		-3.1
Mutation Taster		=91/9	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: rs6442905; hg19: chr3-4817057; COSMIC: COSV108137020; COSMIC: COSV108137020;