rs2073440

chr15-50242317-T-G

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDC	NM_002112.4	c.1932A>C	p.Glu644Asp	missense_variant	12/12	ENST00000267845.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDC	ENST00000267845.8	c.1932A>C	p.Glu644Asp	missense_variant	12/12	1	NM_002112.4	P1
HDC	ENST00000543581.5	c.1833A>C	p.Glu611Asp	missense_variant	11/11	1
HDC	ENST00000559816.1	n.1676A>C		non_coding_transcript_exon_variant	5/5	2

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

GnomAD3 exomes AF: 0.0340 AC: 8552 AN: 251468 Hom.: 305 AF XY: 0.0310 AC XY: 4210 AN XY: 135912

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 SAS exome AF: 0.00947

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

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0248

Gnomad4 EAS exome AF: 0.0674

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.00979

Gnomad4 NFE exome AF: 0.0272

Gnomad4 OTH exome AF: 0.0358

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

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.0920

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.00849

Gnomad4 NFE AF: 0.0274

Gnomad4 OTH AF: 0.0455

Alfa AF: 0.0358 Hom.: 284

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 v4.3

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;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.43	P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.093
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.26	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2073440; hg19: chr15-50534514; COSMIC: COSV51068313; COSMIC: COSV51068313;