NM_001378452.1:c.1926C>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. 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: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• 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

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249812 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135376

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

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	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;.;.
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

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: rs61757106; hg19: chr3-4711377;