2-219055843-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002181.4(IHH):c.600G>A(p.Thr200=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.099 in 1,609,750 control chromosomes in the GnomAD database, including 8,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (803 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7261 hom.)
• Consequence: IHH NM_002181.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.65

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-219055843-C-T is Benign according to our data. Variant chr2-219055843-C-T is described in ClinVar as [Benign]. Clinvar id is 334443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219055843-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IHH	NM_002181.4	c.600G>A	p.Thr200=	synonymous_variant	3/3	ENST00000295731.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IHH	ENST00000295731.7	c.600G>A	p.Thr200=	synonymous_variant	3/3	1	NM_002181.4	P1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15594 AN: 152134 Hom.: 799 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0950

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0962

Gnomad FIN AF: 0.0830

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.100 AC: 24420 AN: 243016 Hom.: 1251 AF XY: 0.0987 AC XY: 13097 AN XY: 132710

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0964

Gnomad EAS exome AF: 0.147

Gnomad SAS exome AF: 0.0904

Gnomad FIN exome AF: 0.0854

Gnomad NFE exome AF: 0.0954

Gnomad OTH exome AF: 0.0991

GnomAD4 exome AF: 0.0986 AC: 143680 AN: 1457498 Hom.: 7261 Cov.: 36 AF XY: 0.0984 AC XY: 71369 AN XY: 725192

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.0962

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.0936

Gnomad4 FIN exome AF: 0.0884

Gnomad4 NFE exome AF: 0.0962

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.103 AC: 15619 AN: 152252 Hom.: 803 Cov.: 32 AF XY: 0.101 AC XY: 7548 AN XY: 74436

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0950

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.0961

Gnomad4 FIN AF: 0.0830

Gnomad4 NFE AF: 0.0976

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0931 Hom.: 747

Bravo AF: 0.106

Asia WGS AF: 0.148 AC: 512 AN: 3478

EpiCase AF: 0.0976

EpiControl AF: 0.0954

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2018	This variant is associated with the following publications: (PMID: 14651602) -

Acrocapitofemoral dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Brachydactyly type A1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.16
Dann	Benign	0.85

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

LitVar

Other links and lift over

dbSNP: rs3731878; hg19: chr2-219920565; COSMIC: COSV55393795; COSMIC: COSV55393795;