2-219055843-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002181.4(IHH):c.600G>A(p.Thr200Thr) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.65

Publications

13 publications found

Variant links:

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]

IHH Gene-Disease associations (from GenCC):

brachydactyly type A1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
acrocapitofemoral dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet

IHH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 334443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
IHH	NM_002181.4 link	c.600G>A	p.Thr200Thr	synonymous_variant	Exon 3 of 3	ENST00000295731.7	NP_002172.2	Q14623

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IHH	ENST00000295731.7 link	c.600G>A	p.Thr200Thr	synonymous_variant	Exon 3 of 3	1	NM_002181.4	ENSP00000295731.5		Q14623

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15594

AN:

152134

Hom.:

799

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.100

AC:

24420

AN:

243016

AF XY:

0.0987

show subpopulations

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 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.:

AF XY:

0.0984

AC XY:

71369

AN XY:

725192

show subpopulations

African (AFR)

AF:

0.119

AC:

3976

AN:

33472

American (AMR)

AF:

0.102

AC:

4571

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0962

AC:

2512

AN:

26110

East Asian (EAS)

AF:

0.163

AC:

6471

AN:

39682

South Asian (SAS)

AF:

0.0936

AC:

8069

AN:

86244

European-Finnish (FIN)

AF:

0.0884

AC:

4370

AN:

49430

Middle Eastern (MID)

AF:

0.0950

AC:

548

AN:

5766

European-Non Finnish (NFE)

AF:

0.0962

AC:

106994

AN:

1111792

Other (OTH)

AF:

0.102

AC:

6169

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

8203

16406

24610

32813

41016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3996

7992

11988

15984

19980

<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

AF:

0.103

AC:

15619

AN:

152252

Hom.:

803

Cov.:

AF XY:

0.101

AC XY:

7548

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.113

AC:

4688

AN:

41542

American (AMR)

AF:

0.0950

AC:

1454

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

359

AN:

3470

East Asian (EAS)

AF:

0.146

AC:

757

AN:

5172

South Asian (SAS)

AF:

0.0961

AC:

463

AN:

4818

European-Finnish (FIN)

AF:

0.0830

AC:

882

AN:

10622

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0976

AC:

6639

AN:

68010

Other (OTH)

AF:

0.116

AC:

244

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

750

1501

2251

3002

3752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0954

Hom.:

967

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 14651602) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Acrocapitofemoral dysplasia

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brachydactyly type A1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.85

PhyloP100

-4.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over