21-36756558-G-C

Variant names:

• chr21-36756558-G-C
• rs146448211
• NM_001352514.2:c.2434C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001352514.2(HLCS):​c.2434C>G​(p.Arg812Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,094 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R812R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.64
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.2434C>G	p.Arg812Gly	missense_variant	Exon 10 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.2434C>G	p.Arg812Gly	missense_variant	Exon 10 of 11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459094 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 725944

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109984

Other (OTH) AF: 0.00 AC: 0 AN: 60204

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	D;.;.
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.42	T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.6	L;L;L
PhyloP100		5.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	.;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.17	.;T;T
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.13	B;B;B
Vest4		0.52
MutPred		0.57		Loss of stability (P = 0.0342);Loss of stability (P = 0.0342);Loss of stability (P = 0.0342);
MVP		0.92
MPC		0.23
ClinPred		0.83	D
GERP RS		3.6
Varity_R		0.25
gMVP		0.49
Mutation Taster		=87/13	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: rs146448211; hg19: chr21-38128859;