rs2051397

Variant names:

• chr21-36749236-T-C
• rs2051397
• NM_001352514.2:c.*5010A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-36749236-T-C
• chr21-36749236-T-G

Variant summary

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

The NM_001352514.2(HLCS):​c.*5010A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 152,520 control chromosomes in the GnomAD database, including 22,621 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 0.54 (22573 hom., cov: 33)
  • Exomes 𝑓: 0.48 (48 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 8 publications found

Genes affected

HLCS (HGNC:4976): (holocarboxylase synthetase) This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

SIM2 (HGNC:10883): (SIM bHLH transcription factor 2) This gene represents a homolog of the Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of neurogenesis. The encoded protein is ubiquitinated by RING-IBR-RING-type E3 ubiquitin ligases, including the parkin RBR E3 ubiquitin protein ligase. This gene maps within the so-called Down syndrome chromosomal region, and is thus thought to contribute to some specific Down syndrome phenotypes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352514.2. 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
	HLCS	NM_001352514.2	MANE Select	c.*5010A>G		3_prime_UTR	Exon 11 of 11	NP_001339443.1
	SIM2	NM_005069.6	MANE Select	c.*1144T>C		3_prime_UTR	Exon 11 of 11	NP_005060.1
	HLCS	NM_000411.8		c.*5010A>G		3_prime_UTR	Exon 12 of 12	NP_000402.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.*5010A>G		3_prime_UTR	Exon 11 of 11	ENSP00000502087.2
	SIM2	ENST00000290399.11	TSL:1 MANE Select	c.*1144T>C		3_prime_UTR	Exon 11 of 11	ENSP00000290399.6

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81898 AN: 151970 Hom.: 22563 Cov.: 33

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.551

GnomAD4 exome AF: 0.479 AC: 208 AN: 434 Hom.: 48 Cov.: 0 AF XY: 0.469 AC XY: 122 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.479 AC: 204 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 3 AN: 6

GnomAD4 genome AF: 0.539 AC: 81931 AN: 152086 Hom.: 22573 Cov.: 33 AF XY: 0.534 AC XY: 39698 AN XY: 74366

African (AFR) AF: 0.519 AC: 21532 AN: 41472

American (AMR) AF: 0.442 AC: 6750 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2218 AN: 3470

East Asian (EAS) AF: 0.285 AC: 1477 AN: 5174

South Asian (SAS) AF: 0.609 AC: 2935 AN: 4822

European-Finnish (FIN) AF: 0.522 AC: 5519 AN: 10582

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.581 AC: 39515 AN: 67966

Other (OTH) AF: 0.545 AC: 1151 AN: 2110

Alfa AF: 0.560 Hom.: 45242

Bravo AF: 0.528

Asia WGS AF: 0.433 AC: 1500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.72
DANN	Benign	0.30
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2051397; hg19: chr21-38121537;