Genetic Variant NM_006497.4:c.512C>A (chr17-2057202-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006497.4(HIC1):c.512C>A(p.Pro171Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000809 in 1,236,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P171R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

HIC1
NM_006497.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.607

Publications

0 publications found

Variant links:

Genes affected

HIC1 (HGNC:4909): (HIC ZBTB transcriptional repressor 1) This gene functions as a growth regulatory and tumor repressor gene. Hypermethylation or deletion of the region of this gene have been associated with tumors and the contiguous-gene syndrome, Miller-Dieker syndrome. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2010]

HIC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.108768106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006497.4. 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
	HIC1	NM_006497.4	MANE Select	c.512C>A	p.Pro171Gln	missense	Exon 2 of 2	NP_006488.2	Q14526-2
	HIC1	NM_001098202.1		c.569C>A	p.Pro190Gln	missense	Exon 2 of 2	NP_001091672.1	Q14526-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HIC1	ENST00000619757.5	TSL:1 MANE Select	c.512C>A	p.Pro171Gln	missense	Exon 2 of 2	ENSP00000477858.1	Q14526-2
HIC1	ENST00000399849.4	TSL:1	c.512C>A	p.Pro171Gln	missense	Exon 2 of 2	ENSP00000382742.2	Q14526-2
HIC1	ENST00000322941.3	TSL:5	c.569C>A	p.Pro190Gln	missense	Exon 2 of 2	ENSP00000314080.3	Q14526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.09e-7

AC:

AN:

1236722

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

608262

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

24314

American (AMR)

AF:

0.00

AC:

AN:

16136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18914

East Asian (EAS)

AF:

0.00

AC:

AN:

25990

South Asian (SAS)

AF:

0.00

AC:

AN:

61256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3570

European-Non Finnish (NFE)

AF:

9.94e-7

AC:

AN:

1005854

Other (OTH)

AF:

0.00

AC:

AN:

50196

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.19

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

0.61

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.62

REVEL

Benign

0.035

Sift

Benign

0.11

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.18

MutPred

0.18

Gain of solvent accessibility (P = 0.0109)

MVP

0.22

ClinPred

0.11

GERP RS

2.5

Varity_R

0.071

gMVP

0.43

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over