NM_001486.4:c.230A>G

Variant names:

• chr2-27497575-A-G
• rs8179206
• NM_001486.4:c.230A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001486.4(GCKR):​c.230A>G​(p.Glu77Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00068 in 1,612,790 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E77K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (11 hom.)
• Consequence: GCKR NM_001486.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.82
• Publications: 20 publications found

Genes affected

GCKR (HGNC:4196): (glucokinase regulator) This gene encodes a protein belonging to the GCKR subfamily of the SIS (Sugar ISomerase) family of proteins. The gene product is a regulatory protein that inhibits glucokinase in liver and pancreatic islet cells by binding non-covalently to form an inactive complex with the enzyme. This gene is considered a susceptibility gene candidate for a form of maturity-onset diabetes of the young (MODY). [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005439669).
• BP6: Variant 2-27497575-A-G is Benign according to our data. Variant chr2-27497575-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225371.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000939 (143/152296) while in subpopulation EAS AF = 0.0215 (111/5174). AF 95% confidence interval is 0.0182. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001486.4. 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
	GCKR	NM_001486.4	MANE Select	c.230A>G	p.Glu77Gly	missense	Exon 3 of 19	NP_001477.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCKR	ENST00000264717.7	TSL:1 MANE Select	c.230A>G	p.Glu77Gly	missense	Exon 3 of 19	ENSP00000264717.2
	GCKR	ENST00000472290.1	TSL:1	n.252A>G		non_coding_transcript_exon	Exon 3 of 11
	GCKR	ENST00000867122.1		c.230A>G	p.Glu77Gly	missense	Exon 3 of 19	ENSP00000537181.1

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00191 AC: 480 AN: 251482 AF XY: 0.00174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0241

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000653 AC: 954 AN: 1460494 Hom.: 11 Cov.: 30 AF XY: 0.000670 AC XY: 487 AN XY: 726656

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.000134 AC: 6 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0187 AC: 744 AN: 39692

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86212

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1110764

Other (OTH) AF: 0.000994 AC: 60 AN: 60356

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74470

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.00105 AC: 16 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0215 AC: 111 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000582 Hom.: 2

Bravo AF: 0.00156

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00194 AC: 235

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 5 (1)
-	-	1	GCKR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.85	T
PhyloP100		3.8
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.16
Sift	Uncertain	0.020	D
Sift4G	Benign	0.064	T
Vest4		0.36
MPC		0.20
ClinPred		0.054	T
GERP RS		3.1
PromoterAI		0.016	Neutral
gMVP		0.31
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs8179206; hg19: chr2-27720442; COSMIC: COSV53021480; COSMIC: COSV53021480;