2-219055032-G-C

Position:

• chr2-219055032-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002181.4(IHH):​c.*175C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 682,856 control chromosomes in the GnomAD database, including 128,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23395 hom., cov: 33)
  • Exomes 𝑓: 0.62 (104880 hom.)
• Consequence: IHH NM_002181.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.481

Genes affected

IHH (HGNC:5956): (Indian hedgehog signaling molecule) This gene encodes a member of the hedgehog family of proteins. The encoded preproprotein is proteolytically processed to generate multiple protein products, including an N-terminal fragment that is involved in signaling. Hedgehog family proteins are essential secreted signaling molecules that regulate a variety of developmental processes including growth, patterning and morphogenesis. The protein encoded by this gene specifically plays a role in bone growth and differentiation. Mutations in this gene are the cause of brachydactyly type A1, which is characterized by shortening or malformation of the fingers and toes. Mutations in this gene are also the cause of acrocapitofemoral dysplasia. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-219055032-G-C is Benign according to our data. Variant chr2-219055032-G-C is described in ClinVar as [Benign]. Clinvar id is 334429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IHH	NM_002181.4	c.*175C>G		3_prime_UTR_variant	3/3	ENST00000295731.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IHH	ENST00000295731.7	c.*175C>G		3_prime_UTR_variant	3/3	1	NM_002181.4	P1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79355 AN: 152024 Hom.: 23399 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.510

GnomAD4 exome AF: 0.616 AC: 327039 AN: 530714 Hom.: 104880 Cov.: 6 AF XY: 0.615 AC XY: 169551 AN XY: 275736

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.509

Gnomad4 ASJ exome AF: 0.622

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.553

Gnomad4 FIN exome AF: 0.736

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.585

GnomAD4 genome AF: 0.522 AC: 79355 AN: 152142 Hom.: 23395 Cov.: 33 AF XY: 0.525 AC XY: 39019 AN XY: 74380

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.737

Gnomad4 NFE AF: 0.665

Gnomad4 OTH AF: 0.505

Alfa AF: 0.485 Hom.: 1669

Bravo AF: 0.490

Asia WGS AF: 0.330 AC: 1151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brachydactyly type A1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.67

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

LitVar

Other links and lift over

dbSNP: rs3099; hg19: chr2-219919754;