12-66306381-C-G

Variant names:

• chr12-66306381-C-G
• rs780083932
• NM_001370285.1:c.644C>G

Variant summary

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

The NM_001370285.1(HELB):​c.644C>G​(p.Pro215Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,445,878 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P215L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HELB NM_001370285.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75
• Publications: 0 publications found

Genes affected

HELB (HGNC:17196): (DNA helicase B) This gene encodes a DNA-dependent ATPase which catalyzes the unwinding of DNA necessary for DNA replication, repair, recombination, and transcription. This gene is thought to function specifically during the S phase entry of the cell cycle. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

HELB Gene-Disease associations (from GenCC):

• familial ovarian carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370285.1. 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
	HELB	NM_001370285.1	MANE Select	c.644C>G	p.Pro215Arg	missense	Exon 3 of 13	NP_001357214.1	Q8NG08-1
	HELB	NM_033647.5		c.644C>G	p.Pro215Arg	missense	Exon 3 of 14	NP_387467.2
	HELB	NR_135080.2		n.755C>G		non_coding_transcript_exon	Exon 3 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELB	ENST00000247815.9	TSL:1 MANE Select	c.644C>G	p.Pro215Arg	missense	Exon 3 of 13	ENSP00000247815.5	Q8NG08-1
	HELB	ENST00000440906.6	TSL:1	n.644C>G		non_coding_transcript_exon	Exon 3 of 12	ENSP00000396955.2	Q8NG08-2
	HELB	ENST00000542394.5	TSL:1	n.644C>G		non_coding_transcript_exon	Exon 3 of 13	ENSP00000439617.1	F5H1I4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 240054 AF XY: 0.00000768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445878 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 719152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32720

American (AMR) AF: 0.00 AC: 0 AN: 42106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 38816

South Asian (SAS) AF: 0.00 AC: 0 AN: 83030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104906

Other (OTH) AF: 0.00 AC: 0 AN: 59664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.48		Gain of catalytic residue at P215 (P = 0.0076)
MVP		0.70
MPC		0.70
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.77
gMVP		0.84
Mutation Taster		=57/43	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: rs780083932; hg19: chr12-66700161;