rs2230182

Variant names:

• chr21-36937160-G-A
• rs2230182
• NM_001352514.2:c.726C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001352514.2(HLCS):​c.726C>T​(p.Pro242Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,046 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (14 hom.)
• Consequence: HLCS NM_001352514.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.26
• Publications: 0 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]

HLCS Gene-Disease associations (from GenCC):

• holocarboxylase synthetase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 21-36937160-G-A is Benign according to our data. Variant chr21-36937160-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00542 (824/152168) while in subpopulation AFR AF = 0.018 (745/41502). AF 95% confidence interval is 0.0169. There are 10 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	NM_001352514.2	MANE Select	c.726C>T	p.Pro242Pro	synonymous	Exon 4 of 11	NP_001339443.1
	HLCS	NM_000411.8		c.285C>T	p.Pro95Pro	synonymous	Exon 5 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.285C>T	p.Pro95Pro	synonymous	Exon 5 of 12	NP_001229713.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.726C>T	p.Pro242Pro	synonymous	Exon 4 of 11	ENSP00000502087.2
	HLCS	ENST00000336648.8	TSL:1	c.285C>T	p.Pro95Pro	synonymous	Exon 5 of 12	ENSP00000338387.3
	HLCS	ENST00000399120.5	TSL:1	c.285C>T	p.Pro95Pro	synonymous	Exon 5 of 12	ENSP00000382071.1

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 820 AN: 152050 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00167 AC: 420 AN: 251438 AF XY: 0.00135

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000843 AC: 1233 AN: 1461878 Hom.: 14 Cov.: 34 AF XY: 0.000752 AC XY: 547 AN XY: 727236

African (AFR) AF: 0.0214 AC: 717 AN: 33478

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.000185 AC: 206 AN: 1112004

Other (OTH) AF: 0.00233 AC: 141 AN: 60396

GnomAD4 genome AF: 0.00542 AC: 824 AN: 152168 Hom.: 10 Cov.: 32 AF XY: 0.00524 AC XY: 390 AN XY: 74402

African (AFR) AF: 0.0180 AC: 745 AN: 41502

American (AMR) AF: 0.00340 AC: 52 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67998

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00327 Hom.: 7

Bravo AF: 0.00632

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Holocarboxylase synthetase deficiency (4)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.18
DANN	Benign	0.48
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

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: rs2230182; hg19: chr21-38309460;