3-4669693-C-G

Variant names:

• chr3-4669693-C-G
• rs61757106
• NM_001378452.1:c.1926C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378452.1(ITPR1):​c.1926C>G​(p.Asn642Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. N642N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• Publications: 2 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: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2026672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.1926C>G	p.Asn642Lys	missense_variant	Exon 19 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.1881C>G	p.Asn627Lys	missense_variant	Exon 18 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.1926C>G	p.Asn642Lys	missense_variant	Exon 19 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.1881C>G	p.Asn627Lys	missense_variant	Exon 18 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.1926C>G	p.Asn642Lys	missense_variant	Exon 19 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.1926C>G	p.Asn642Lys	missense_variant	Exon 19 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.1926C>G	p.Asn642Lys	missense_variant	Exon 19 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.1881C>G	p.Asn627Lys	missense_variant	Exon 18 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.1881C>G	p.Asn627Lys	missense_variant	Exon 18 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.1881C>G	p.Asn627Lys	missense_variant	Exon 16 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.1926C>G	p.Asn642Lys	missense_variant	Exon 19 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.1881C>G	p.Asn627Lys	missense_variant	Exon 18 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249812 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.85e-7 AC: 1 AN: 1460860 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726740

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111276

Other (OTH) AF: 0.00 AC: 0 AN: 60314

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	Uncertain	0.49
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.38
DEOGEN2	Uncertain	0.66	.;.;.;.;.;.;D;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.17	N;.;.;.;.;.;N;.;.
PhyloP100		1.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.47	N;N;N;N;.;.;.;.;N
REVEL	Benign	0.28
Sift	Benign	0.87	T;T;T;T;.;.;.;.;T
Sift4G	Benign	0.89	T;T;.;T;.;.;.;.;T
Polyphen		0.0030	.;.;.;.;.;.;B;.;.
Vest4		0.53
MutPred		0.62		Gain of catalytic residue at N642 (P = 0.0155);.;Gain of catalytic residue at N642 (P = 0.0155);.;Gain of catalytic residue at N642 (P = 0.0155);.;Gain of catalytic residue at N642 (P = 0.0155);.;.;
MVP		0.69
MPC		1.2
ClinPred		0.14	T
GERP RS		4.4
Varity_R		0.076
gMVP		0.82
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs61757106; hg19: chr3-4711377;