19-45669554-C-G

Variant summary

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

The NM_000164.4(GIPR):c.34C>G(p.Arg12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000049 in 1,429,818 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: GIPR NM_000164.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.230

Genes affected

GIPR (HGNC:4271): (gastric inhibitory polypeptide receptor) This gene encodes a G-protein coupled receptor for gastric inhibitory polypeptide (GIP), which was originally identified as an activity in gut extracts that inhibited gastric acid secretion and gastrin release, but subsequently was demonstrated to stimulate insulin release in the presence of elevated glucose. Mice lacking this gene exhibit higher blood glucose levels with impaired initial insulin response after oral glucose load. Defect in this gene thus may contribute to the pathogenesis of diabetes. [provided by RefSeq, Oct 2011]

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=0.100287735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPR	NM_000164.4	c.34C>G	p.Arg12Gly	missense_variant	2/14	ENST00000590918.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPR	ENST00000590918.6	c.34C>G	p.Arg12Gly	missense_variant	2/14	1	NM_000164.4	P2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000490 AC: 7 AN: 1429818 Hom.: 0 Cov.: 31 AF XY: 0.00000847 AC XY: 6 AN XY: 708636

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: 0.00000637

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.34C>G (p.R12G) alteration is located in exon 2 (coding exon 1) of the GIPR gene. This alteration results from a C to G substitution at nucleotide position 34, causing the arginine (R) at amino acid position 12 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.013	B;B;.
Vest4		0.17
MutPred		0.49		Loss of methylation at R12 (P = 0.0587);Loss of methylation at R12 (P = 0.0587);Loss of methylation at R12 (P = 0.0587);
MVP		0.36
MPC		0.95
ClinPred		0.76	D
GERP RS		0.32
Varity_R		0.13
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1975427515; hg19: chr19-46172812;