rs222016

Variant names:

• chr4-71769258-G-A
• rs222016
• NM_000583.4:c.128+73C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000583.4(GC):​c.128+73C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 1,138,650 control chromosomes in the GnomAD database, including 380,913 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (42415 hom., cov: 31)
  • Exomes 𝑓: 0.82 (338498 hom.)
• Consequence: GC NM_000583.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 21 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GC	NM_000583.4	c.128+73C>T		intron_variant	Intron 2 of 12	ENST00000273951.13	NP_000574.2
GC	NM_001204307.1	c.185+73C>T		intron_variant	Intron 3 of 13		NP_001191236.1
GC	NM_001204306.1	c.128+73C>T		intron_variant	Intron 3 of 13		NP_001191235.1
GC	NM_001440458.1	c.128+73C>T		intron_variant	Intron 2 of 11		NP_001427387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GC	ENST00000273951.13	c.128+73C>T		intron_variant	Intron 2 of 12	1	NM_000583.4	ENSP00000273951.8

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110428 AN: 151892 Hom.: 42411 Cov.: 31

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.854

Gnomad FIN AF: 0.796

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.850

Gnomad OTH AF: 0.758

GnomAD4 exome AF: 0.825 AC: 813767 AN: 986640 Hom.: 338498 AF XY: 0.828 AC XY: 420290 AN XY: 507504

African (AFR) AF: 0.456 AC: 11138 AN: 24404

American (AMR) AF: 0.775 AC: 31399 AN: 40510

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 20019 AN: 22232

East Asian (EAS) AF: 0.643 AC: 23824 AN: 37060

South Asian (SAS) AF: 0.852 AC: 62107 AN: 72938

European-Finnish (FIN) AF: 0.803 AC: 41115 AN: 51174

Middle Eastern (MID) AF: 0.823 AC: 3998 AN: 4856

European-Non Finnish (NFE) AF: 0.848 AC: 584388 AN: 688974

Other (OTH) AF: 0.804 AC: 35779 AN: 44492

GnomAD4 genome AF: 0.727 AC: 110463 AN: 152010 Hom.: 42415 Cov.: 31 AF XY: 0.727 AC XY: 54053 AN XY: 74300

African (AFR) AF: 0.459 AC: 19000 AN: 41420

American (AMR) AF: 0.807 AC: 12327 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3139 AN: 3472

East Asian (EAS) AF: 0.601 AC: 3094 AN: 5148

South Asian (SAS) AF: 0.854 AC: 4113 AN: 4814

European-Finnish (FIN) AF: 0.796 AC: 8430 AN: 10594

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.850 AC: 57782 AN: 67980

Other (OTH) AF: 0.759 AC: 1602 AN: 2112

Alfa AF: 0.805 Hom.: 151720

Bravo AF: 0.709

Asia WGS AF: 0.702 AC: 2442 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.012
DANN	Benign	0.48
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs222016; hg19: chr4-72634975; COSMIC: COSV56737041;