17-2057487-C-G

Variant names:

• chr17-2057487-C-G
• rs776960639
• NM_006497.4:c.797C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006497.4(HIC1):​c.797C>G​(p.Ala266Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,483,958 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A266T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (0 hom.)
• Consequence: HIC1 NM_006497.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.515
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022654623).
• BS2: High AC in GnomAd4 at 83 AD gene.

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.797C>G	p.Ala266Gly	missense	Exon 2 of 2	NP_006488.2	Q14526-2
	HIC1	NM_001098202.1		c.854C>G	p.Ala285Gly	missense	Exon 2 of 2	NP_001091672.1	Q14526-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIC1	ENST00000619757.5	TSL:1 MANE Select	c.797C>G	p.Ala266Gly	missense	Exon 2 of 2	ENSP00000477858.1	Q14526-2
	HIC1	ENST00000399849.4	TSL:1	c.797C>G	p.Ala266Gly	missense	Exon 2 of 2	ENSP00000382742.2	Q14526-2
	HIC1	ENST00000322941.3	TSL:5	c.854C>G	p.Ala285Gly	missense	Exon 2 of 2	ENSP00000314080.3	Q14526-1

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 151906 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000957

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000457 AC: 39 AN: 85382 AF XY: 0.000413

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000542

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000394

GnomAD4 exome AF: 0.000963 AC: 1283 AN: 1332052 Hom.: 0 Cov.: 32 AF XY: 0.000906 AC XY: 595 AN XY: 656712

African (AFR) AF: 0.0000373 AC: 1 AN: 26814

American (AMR) AF: 0.0000334 AC: 1 AN: 29964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23432

East Asian (EAS) AF: 0.00 AC: 0 AN: 28756

South Asian (SAS) AF: 0.00 AC: 0 AN: 74658

European-Finnish (FIN) AF: 0.000515 AC: 17 AN: 33020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4400

European-Non Finnish (NFE) AF: 0.00117 AC: 1230 AN: 1055720

Other (OTH) AF: 0.000615 AC: 34 AN: 55288

GnomAD4 genome AF: 0.000546 AC: 83 AN: 151906 Hom.: 0 Cov.: 33 AF XY: 0.000512 AC XY: 38 AN XY: 74204

African (AFR) AF: 0.000314 AC: 13 AN: 41422

American (AMR) AF: 0.000197 AC: 3 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000957 AC: 65 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000654 Hom.: 1

Bravo AF: 0.000499

ExAC AF: 0.000204 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.33	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.52
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.24	N
REVEL	Benign	0.030
Sift	Benign	0.43	T
Sift4G	Benign	0.39	T
Polyphen		0.041	B
Vest4		0.13
MVP		0.15
ClinPred		0.016	T
GERP RS		3.0
Varity_R		0.032
gMVP		0.077
Mutation Taster		=90/10	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: rs776960639; hg19: chr17-1960781;