17-2057235-C-T

Variant names:

• chr17-2057235-C-T
• rs1467802380
• NM_006497.4:c.545C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006497.4(HIC1):​c.545C>T​(p.Ala182Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,269,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A182G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: HIC1 NM_006497.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.193
• Publications: 0 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: 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=0.10027537).

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.545C>T	p.Ala182Val	missense	Exon 2 of 2	NP_006488.2	Q14526-2
	HIC1	NM_001098202.1		c.602C>T	p.Ala201Val	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.545C>T	p.Ala182Val	missense	Exon 2 of 2	ENSP00000477858.1	Q14526-2
	HIC1	ENST00000399849.4	TSL:1	c.545C>T	p.Ala182Val	missense	Exon 2 of 2	ENSP00000382742.2	Q14526-2
	HIC1	ENST00000322941.3	TSL:5	c.602C>T	p.Ala201Val	missense	Exon 2 of 2	ENSP00000314080.3	Q14526-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000315 AC: 4 AN: 1269644 Hom.: 0 Cov.: 32 AF XY: 0.00000160 AC XY: 1 AN XY: 626234

African (AFR) AF: 0.00 AC: 0 AN: 25072

American (AMR) AF: 0.00 AC: 0 AN: 19314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20770

East Asian (EAS) AF: 0.0000378 AC: 1 AN: 26430

South Asian (SAS) AF: 0.00 AC: 0 AN: 67640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3740

European-Non Finnish (NFE) AF: 9.77e-7 AC: 1 AN: 1023276

Other (OTH) AF: 0.0000387 AC: 2 AN: 51690

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.19
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.013
Sift	Benign	0.22	T
Sift4G	Benign	0.29	T
Polyphen		0.43	B
Vest4		0.11
MutPred		0.24		Gain of catalytic residue at A201 (P = 0.0099)
MVP		0.17
ClinPred		0.11	T
GERP RS		2.3
Varity_R		0.027
gMVP		0.25
Mutation Taster		=92/8	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: rs1467802380; hg19: chr17-1960529;