17-81810917-C-T

Position:

• chr17-81810917-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS1_Moderate PM2 PP5

The NM_000160.5(GCGR):​c.256C>T​(p.Pro86Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,384,382 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCGR NM_000160.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.57

Genes affected

GCGR (HGNC:4192): (glucagon receptor) The protein encoded by this gene is a glucagon receptor that is important in controlling blood glucose levels. Defects in this gene are a cause of non-insulin-dependent diabetes mellitus (NIDDM).[provided by RefSeq, Jan 2010]

GCGR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PS1: Transcript NM_000160.5 (GCGR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-81810917-C-T is Pathogenic according to our data. Variant chr17-81810917-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1064733.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCGR	NM_000160.5	c.256C>T	p.Pro86Ser	missense_variant	4/14	ENST00000400723.8	NP_000151.1
GCGR	XM_006722277.2	c.256C>T	p.Pro86Ser	missense_variant	4/14		XP_006722340.1
GCGR	XM_017024446.2	c.250C>T	p.Pro84Ser	missense_variant	4/14		XP_016879935.1
GCGR	XM_011523539.2	c.172+8C>T		splice_region_variant, intron_variant			XP_011521841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCGR	ENST00000400723.8	c.256C>T	p.Pro86Ser	missense_variant	4/14	1	NM_000160.5	ENSP00000383558.3
GCGR	ENST00000570996.5	c.256C>T	p.Pro86Ser	missense_variant	4/12	2		ENSP00000460976.1
GCGR	ENST00000574283.2	n.340C>T		non_coding_transcript_exon_variant	2/3	5
GCGR	ENST00000573428.1	c.*16C>T		downstream_gene_variant		4		ENSP00000458930.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1384382 Hom.: 0 Cov.: 44 AF XY: 0.00000146 AC XY: 1 AN XY: 683150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

GCGR-related hyperglucagonemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.4	D;.
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0030	D;T
Polyphen		1.0	D;.
Vest4		0.39
MutPred		0.51		Gain of MoRF binding (P = 0.0451);Gain of MoRF binding (P = 0.0451);
MVP		0.86
MPC		0.0087
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.94
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-79768793;