Genetic Variant GC:p.Thr436Lys (chr4-71752606-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000583.4(GC):c.1307C>A(p.Thr436Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,612,616 control chromosomes in the GnomAD database, including 62,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.22 ( 4369 hom., cov: 32)

Exomes 𝑓: 0.28 ( 57776 hom. )

Consequence

GC
NM_000583.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: -0.459

Variant links:

Genes affected

GC (HGNC:4187): (GC vitamin D binding protein) The protein encoded by this gene belongs to the albumin gene family. It is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types. It binds to vitamin D and its plasma metabolites and transports them to target tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

GC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004927546).

BP6

Variant 4-71752606-G-T is Benign according to our data. Variant chr4-71752606-G-T is described in ClinVar as [Benign]. Clinvar id is 15986.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GC	NM_000583.4 link	c.1307C>A	p.Thr436Lys	missense_variant	Exon 11 of 13	ENST00000273951.13	NP_000574.2	P02774-1
GC	NM_001204307.1 link	c.1364C>A	p.Thr455Lys	missense_variant	Exon 12 of 14		NP_001191236.1	P02774-3
GC	NM_001204306.1 link	c.1307C>A	p.Thr436Lys	missense_variant	Exon 12 of 14		NP_001191235.1	P02774-1
GC	XM_006714177.3 link	c.1262+1805C>A		intron_variant	Intron 10 of 11		XP_006714240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GC	ENST00000273951.13 link	c.1307C>A	p.Thr436Lys	missense_variant	Exon 11 of 13	1	NM_000583.4	ENSP00000273951.8		P02774-1

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33938

AN:

152010

Hom.:

4364

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.411

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.288

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.286

Gnomad FIN

AF:

0.197

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.288

Gnomad OTH

AF:

0.236

GnomAD3 exomes

AF:

0.253

AC:

63579

AN:

251214

Hom.:

8454

AF XY:

0.260

AC XY:

35363

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.0981

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.285

Gnomad EAS exome

AF:

0.272

Gnomad SAS exome

AF:

0.298

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.278

AC:

406250

AN:

1460488

Hom.:

57776

Cov.:

AF XY:

0.279

AC XY:

203015

AN XY:

726636

show subpopulations

Gnomad4 AFR exome

AF:

0.0963

Gnomad4 AMR exome

AF:

0.211

Gnomad4 ASJ exome

AF:

0.288

Gnomad4 EAS exome

AF:

0.268

Gnomad4 SAS exome

AF:

0.298

Gnomad4 FIN exome

AF:

0.203

Gnomad4 NFE exome

AF:

0.290

Gnomad4 OTH exome

AF:

0.262

GnomAD4 genome

AF:

0.223

AC:

33964

AN:

152128

Hom.:

4369

Cov.:

AF XY:

0.219

AC XY:

16279

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.222

Gnomad4 ASJ

AF:

0.288

Gnomad4 EAS

AF:

0.256

Gnomad4 SAS

AF:

0.288

Gnomad4 FIN

AF:

0.197

Gnomad4 NFE

AF:

0.288

Gnomad4 OTH

AF:

0.239

Alfa

AF:

0.271

Hom.:

12488

Bravo

AF:

0.219

TwinsUK

AF:

0.292

AC:

1082

ALSPAC

AF:

0.288

AC:

1110

ESP6500AA

AF:

0.106

AC:

467

ESP6500EA

AF:

0.289

AC:

2489

ExAC

AF:

0.253

AC:

30677

Asia WGS

AF:

0.232

AC:

811

AN:

3478

EpiCase

AF:

0.286

EpiControl

AF:

0.282

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

GC1/GC2 POLYMORPHISM

Benign:1

Jun 01, 1992

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Levothyroxine response

Other:1

Pharmacogenomics/Precision medicine lab, University of Petra

Significance: other

Review Status: no assertion criteria provided

Collection Method: research

- The snp had no effect on levothyroxine dosage requirement nor thyroid hormone levels in our study

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.078

DANN

Benign

0.19

DEOGEN2

Benign

0.0029

.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.16

T;T;T

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-0.94

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.12

N;N;N

REVEL

Benign

0.0070

Sift

Benign

0.48

T;T;T

Sift4G

Benign

0.87

T;T;T

Polyphen

0.0090

.;.;B

Vest4

0.080

MPC

0.060

ClinPred

0.00012

GERP RS

-2.7

Varity_R

0.10

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over