7-44149977-G-T

Variant names:

• chr7-44149977-G-T
• rs1085307455
• NM_000162.5:c.571C>A
• GCK p.Arg191Arg

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_ModerateBP7

The NM_000162.5(GCK):c.571C>A (p.Arg191Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000479 (AC=7) in the gnomAD database across 1,461,634 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000262. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GCK NM_000162.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.949
• Publications: 34 publications found

Genes affected

GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]

GCK Gene-Disease associations (from GenCC):

• hyperinsulinemic hypoglycemia, familial, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• monogenic diabetes

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• type 2 diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300758 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Specifications for GCK are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000262 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000162.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GCK NM_000162.5	MANE Select	c.571C>A p.Arg191Arg	synonymous	Exon 5 of 10	Prot: NP_000153.1 UniProt:
	GCK NM_033507.3		c.574C>A p.Arg192Arg	synonymous	Exon 5 of 10	Prot: NP_277042.1 UniProt:
	GCK NM_033508.3		c.568C>A p.Arg190Arg	synonymous	Exon 6 of 11	Prot: NP_277043.1 UniProt:

GCK NM_000162.5

MANE Select

HGVSc / HGVSpc.571C>Ap.Arg191Arg

Exon rankExon 5 of 10

synonymous

Prot: NP_000153.1UniProt: P35557-1Q53Y25

GCK NM_033507.3

HGVSc / HGVSpc.574C>Ap.Arg192Arg

Exon rankExon 5 of 10

synonymous

Prot: NP_277042.1UniProt: P35557-2

GCK NM_033508.3

HGVSc / HGVSpc.568C>Ap.Arg190Arg

Exon rankExon 6 of 11

synonymous

Prot: NP_277043.1UniProt: P35557-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GCK ENST00000403799.8	TSL:1MANE Select	c.571C>A p.Arg191Arg	synonymous	Exon 5 of 10	Prot: ENSP00000384247.3 UniProt:
	GCK ENST00000395796.8	TSL:1	n.*569C>A	3_prime_UTR	Exon 6 of 11	Prot: ENSP00000379142.4 UniProt:
	GCK ENST00000395796.8	TSL:1	n.*569C>A	non_coding_transcript_exon	Exon 6 of 11	Prot: ENSP00000379142.4 UniProt:

GCK ENST00000403799.8

TSL:1MANE Select

HGVSc / HGVSpc.571C>Ap.Arg191Arg

Exon rankExon 5 of 10

synonymous

Prot: ENSP00000384247.3UniProt: P35557-1

GCK ENST00000395796.8

TSL:1

HGVSc / HGVSpn.*569C>A

Exon rankExon 6 of 11

3_prime_UTR

Prot: ENSP00000379142.4UniProt: A0A8C8KJG0

GCK ENST00000395796.8

TSL:1

HGVSc / HGVSpn.*569C>A

Exon rankExon 6 of 11

non_coding_transcript_exon

Prot: ENSP00000379142.4UniProt: A0A8C8KJG0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF: 0.00000479	AC:7	Hom:0	AN:1461634	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16838	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.1
DANN	Benign	0.66
GPN-Star LLR	N/A	-3.5
GPN-Star score	N/A	3.5
PhyloP100	Benign	0.95

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.080
SpliceAI score (max)	Benign	0.060	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1085307455;

hg19: chr7-44189576;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar