rs2051397

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.*5010A>G		3_prime_UTR_variant	11/11	ENST00000674895.3	NP_001339443.1
SIM2	NM_005069.6	c.*1144T>C		3_prime_UTR_variant	11/11	ENST00000290399.11	NP_005060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.*1144T>C		3_prime_UTR_variant	11/11	1	NM_005069.6	ENSP00000290399	P1
HLCS	ENST00000674895.3	c.*5010A>G		3_prime_UTR_variant	11/11		NM_001352514.2	ENSP00000502087	P4

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

Gnomad4 FIN exome AF: 0.479

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

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

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.285

Gnomad4 SAS AF: 0.609

Gnomad4 FIN AF: 0.522

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.545

Alfa AF: 0.566 Hom.: 33305

Bravo AF: 0.528

Asia WGS AF: 0.433 AC: 1500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.72
DANN	Benign	0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs2051397; hg19: chr21-38121537;