12-56042145-C-G

Variant names:

• chr12-56042145-C-G
• rs1131017
• NM_001029.5:c.-22C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001029.5(RPS26):​c.-22C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,612,112 control chromosomes in the GnomAD database, including 280,041 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21890 hom., cov: 32)
  • Exomes 𝑓: 0.59 (258151 hom.)
• Consequence: RPS26 NM_001029.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.358
• Publications: 110 publications found

Genes affected

RPS26 (HGNC:10414): (ribosomal protein S26) This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S26E family of ribosomal proteins. Mutations in this gene are found in Diamond-Blackfan anemia 10. There are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Aug 2017]

RPS26 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-56042145-C-G is Benign according to our data. Variant chr12-56042145-C-G is described in ClinVar as Benign. ClinVar VariationId is 309857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS26	NM_001029.5	MANE Select	c.-22C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001020.2
	RPS26	NM_001029.5	MANE Select	c.-22C>G		5_prime_UTR	Exon 1 of 4	NP_001020.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS26	ENST00000646449.2	MANE Select	c.-22C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000496643.1
	RPS26	ENST00000356464.10	TSL:1	c.-22C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000348849.5
	RPS26	ENST00000646449.2	MANE Select	c.-22C>G		5_prime_UTR	Exon 1 of 4	ENSP00000496643.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76819 AN: 151888 Hom.: 21887 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.560

GnomAD2 exomes AF: 0.617 AC: 154991 AN: 251118 AF XY: 0.623

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.762

Gnomad ASJ exome AF: 0.588

Gnomad EAS exome AF: 0.790

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.586

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.588 AC: 859149 AN: 1460106 Hom.: 258151 Cov.: 43 AF XY: 0.593 AC XY: 430778 AN XY: 726448

African (AFR) AF: 0.214 AC: 7166 AN: 33442

American (AMR) AF: 0.748 AC: 33456 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 15235 AN: 26124

East Asian (EAS) AF: 0.796 AC: 31584 AN: 39690

South Asian (SAS) AF: 0.699 AC: 60245 AN: 86224

European-Finnish (FIN) AF: 0.587 AC: 31336 AN: 53370

Middle Eastern (MID) AF: 0.692 AC: 3991 AN: 5768

European-Non Finnish (NFE) AF: 0.577 AC: 640782 AN: 1110426

Other (OTH) AF: 0.586 AC: 35354 AN: 60344

GnomAD4 genome AF: 0.505 AC: 76834 AN: 152006 Hom.: 21890 Cov.: 32 AF XY: 0.515 AC XY: 38265 AN XY: 74304

African (AFR) AF: 0.226 AC: 9358 AN: 41454

American (AMR) AF: 0.650 AC: 9908 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1978 AN: 3472

East Asian (EAS) AF: 0.780 AC: 4026 AN: 5162

South Asian (SAS) AF: 0.705 AC: 3398 AN: 4818

European-Finnish (FIN) AF: 0.599 AC: 6342 AN: 10582

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.590 AC: 40069 AN: 67960

Other (OTH) AF: 0.560 AC: 1179 AN: 2104

Alfa AF: 0.493 Hom.: 2792

Bravo AF: 0.497

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 10 Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Feb 06, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.4
DANN	Benign	0.58
PhyloP100		0.36
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs1131017; hg19: chr12-56435929;