chr12-66302630-C-A

Variant names:

• chr12-66302630-C-A
• rs3741604
• NM_001370285.1:c.27C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_033647.5(HELB):​c.27C>A​(p.Arg9Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HELB NM_033647.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033647.5. 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.27C>A	p.Arg9Arg	synonymous	Exon 1 of 13	NP_001357214.1
	HELB	NM_033647.5		c.27C>A	p.Arg9Arg	synonymous	Exon 1 of 14	NP_387467.2
	HELB	NR_135080.2		n.138C>A		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELB	ENST00000247815.9	TSL:1 MANE Select	c.27C>A	p.Arg9Arg	synonymous	Exon 1 of 13	ENSP00000247815.5
	HELB	ENST00000440906.6	TSL:1	n.27C>A		non_coding_transcript_exon	Exon 1 of 12	ENSP00000396955.2
	HELB	ENST00000542394.5	TSL:1	n.27C>A		non_coding_transcript_exon	Exon 1 of 13	ENSP00000439617.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461508 Hom.: 0 Cov.: 47 AF XY: 0.00000138 AC XY: 1 AN XY: 727010

⚠️ 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: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111712

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

⚠️ 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
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.8
DANN	Benign	0.54
PhyloP100		-2.3
PromoterAI		-0.028	Neutral

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: rs3741604; hg19: chr12-66696410;