12-66305055-A-C

Variant names:

• chr12-66305055-A-C
• NM_001370285.1:c.512A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001370285.1(HELB):​c.512A>C​(p.Lys171Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HELB NM_001370285.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07139146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELB	NM_001370285.1	c.512A>C	p.Lys171Thr	missense_variant	Exon 2 of 13	ENST00000247815.9	NP_001357214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELB	ENST00000247815.9	c.512A>C	p.Lys171Thr	missense_variant	Exon 2 of 13	1	NM_001370285.1	ENSP00000247815.5
HELB	ENST00000440906.6	n.512A>C		non_coding_transcript_exon_variant	Exon 2 of 12	1		ENSP00000396955.2
HELB	ENST00000542394.5	n.512A>C		non_coding_transcript_exon_variant	Exon 2 of 13	1		ENSP00000439617.1
HELB	ENST00000545134.1	n.512A>C		non_coding_transcript_exon_variant	Exon 2 of 14	2		ENSP00000443287.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.512A>C (p.K171T) alteration is located in exon 2 (coding exon 2) of the HELB gene. This alteration results from a A to C substitution at nucleotide position 512, causing the lysine (K) at amino acid position 171 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.2
DANN	Benign	0.95
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.080	N
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.012
Sift	Benign	0.047	D
Sift4G	Benign	0.29	T
Polyphen		0.26	B
Vest4		0.14
MutPred		0.23		Gain of ubiquitination at K176 (P = 0.0177);
MVP		0.18
MPC		0.19
ClinPred		0.086	T
GERP RS		0.56
Varity_R		0.066
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-66698835;