rs2073440

Variant names:

• chr15-50242317-T-G
• rs2073440
• NM_002112.4:c.1932A>C

Variant summary

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

The NM_002112.4(HDC):​c.1932A>C​(p.Glu644Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,614,018 control chromosomes in the GnomAD database, including 1,376 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.058 (459 hom., cov: 32)
  • Exomes 𝑓: 0.029 (917 hom.)
• Consequence: HDC NM_002112.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.870
• Publications: 21 publications found

Genes affected

HDC (HGNC:4855): (histidine decarboxylase) This gene encodes a member of the group II decarboxylase family and forms a homodimer that converts L-histidine to histamine in a pyridoxal phosphate dependent manner. Histamine regulates several physiologic processes, including neurotransmission, gastric acid secretion,inflamation, and smooth muscle tone.[provided by RefSeq, Aug 2010]

HDC Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015276372).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002112.4. 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
	HDC	NM_002112.4	MANE Select	c.1932A>C	p.Glu644Asp	missense	Exon 12 of 12	NP_002103.2	P19113-1
	HDC	NM_001306146.2		c.1833A>C	p.Glu611Asp	missense	Exon 11 of 11	NP_001293075.1	P19113-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDC	ENST00000267845.8	TSL:1 MANE Select	c.1932A>C	p.Glu644Asp	missense	Exon 12 of 12	ENSP00000267845.3	P19113-1
	HDC	ENST00000543581.5	TSL:1	c.1833A>C	p.Glu611Asp	missense	Exon 11 of 11	ENSP00000440252.1	P19113-2
	HDC	ENST00000860523.1		c.2037A>C	p.Glu679Asp	missense	Exon 12 of 12	ENSP00000530582.1

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8750 AN: 152072 Hom.: 456 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.00849

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0460

GnomAD2 exomes AF: 0.0340 AC: 8552 AN: 251468 AF XY: 0.0310

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.0931

Gnomad FIN exome AF: 0.00836

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0293 AC: 42842 AN: 1461828 Hom.: 917 Cov.: 32 AF XY: 0.0283 AC XY: 20596 AN XY: 727226

African (AFR) AF: 0.139 AC: 4665 AN: 33470

American (AMR) AF: 0.0192 AC: 858 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 648 AN: 26136

East Asian (EAS) AF: 0.0674 AC: 2675 AN: 39698

South Asian (SAS) AF: 0.0108 AC: 932 AN: 86256

European-Finnish (FIN) AF: 0.00979 AC: 523 AN: 53420

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5768

European-Non Finnish (NFE) AF: 0.0272 AC: 30247 AN: 1111960

Other (OTH) AF: 0.0358 AC: 2162 AN: 60396

GnomAD4 genome AF: 0.0576 AC: 8766 AN: 152190 Hom.: 459 Cov.: 32 AF XY: 0.0544 AC XY: 4044 AN XY: 74396

African (AFR) AF: 0.136 AC: 5661 AN: 41510

American (AMR) AF: 0.0277 AC: 423 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3464

East Asian (EAS) AF: 0.0920 AC: 476 AN: 5174

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4822

European-Finnish (FIN) AF: 0.00849 AC: 90 AN: 10606

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0274 AC: 1861 AN: 68010

Other (OTH) AF: 0.0455 AC: 96 AN: 2110

Alfa AF: 0.0378 Hom.: 605

Bravo AF: 0.0632

TwinsUK AF: 0.0275 AC: 102

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.127 AC: 558

ESP6500EA AF: 0.0279 AC: 240

ExAC AF: 0.0368 AC: 4471

Asia WGS AF: 0.0570 AC: 201 AN: 3478

EpiCase AF: 0.0285

EpiControl AF: 0.0272

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.87
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.093
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.26	T
Polyphen		0.92	P
Vest4		0.20
MutPred		0.18		Gain of catalytic residue at E644 (P = 0.1443)
MPC		0.36
ClinPred		0.022	T
GERP RS		-0.98
Varity_R		0.082
gMVP		0.41
Mutation Taster		=99/1	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: rs2073440; hg19: chr15-50534514; COSMIC: COSV51068313; COSMIC: COSV51068313;