2-219055315-A-G

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.1128T>C(p.Thr376Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.815 in 1,612,922 control chromosomes in the GnomAD database, including 537,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 56256 hom., cov: 35)

Exomes 𝑓: 0.81 ( 481539 hom. )

Consequence

IHH
NM_002181.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.798

Publications

22 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=-0.8).

BP6

Variant 2-219055315-A-G is Benign according to our data. Variant chr2-219055315-A-G is described in ClinVar as Benign. ClinVar VariationId is 593247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.798 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002181.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHH	NM_002181.4	MANE Select	c.1128T>C	p.Thr376Thr	synonymous	Exon 3 of 3	NP_002172.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHH	ENST00000295731.7	TSL:1 MANE Select	c.1128T>C	p.Thr376Thr	synonymous	Exon 3 of 3	ENSP00000295731.5

Frequencies

GnomAD3 genomes

AF:

0.856

AC:

130272

AN:

152186

Hom.:

56199

Cov.:

show subpopulations

Gnomad AFR

AF:

0.961

Gnomad AMI

AF:

0.707

Gnomad AMR

AF:

0.836

Gnomad ASJ

AF:

0.749

Gnomad EAS

AF:

0.907

Gnomad SAS

AF:

0.822

Gnomad FIN

AF:

0.875

Gnomad MID

AF:

0.718

Gnomad NFE

AF:

0.801

Gnomad OTH

AF:

0.828

GnomAD2 exomes

AF:

0.835

AC:

207168

AN:

248116

AF XY:

0.829

show subpopulations

Gnomad AFR exome

AF:

0.965

Gnomad AMR exome

AF:

0.867

Gnomad ASJ exome

AF:

0.749

Gnomad EAS exome

AF:

0.919

Gnomad FIN exome

AF:

0.878

Gnomad NFE exome

AF:

0.800

Gnomad OTH exome

AF:

0.796

GnomAD4 exome

AF:

0.811

AC:

1184656

AN:

1460618

Hom.:

481539

Cov.:

AF XY:

0.810

AC XY:

588270

AN XY:

726596

show subpopulations

African (AFR)

AF:

0.962

AC:

32190

AN:

33476

American (AMR)

AF:

0.859

AC:

38398

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.749

AC:

19565

AN:

26128

East Asian (EAS)

AF:

0.877

AC:

34792

AN:

39692

South Asian (SAS)

AF:

0.813

AC:

70127

AN:

86238

European-Finnish (FIN)

AF:

0.876

AC:

45929

AN:

52418

Middle Eastern (MID)

AF:

0.724

AC:

4175

AN:

5766

European-Non Finnish (NFE)

AF:

0.801

AC:

890392

AN:

1111820

Other (OTH)

AF:

0.813

AC:

49088

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

14437

28874

43310

57747

72184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20826

41652

62478

83304

104130

<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:

0.856

AC:

130387

AN:

152304

Hom.:

56256

Cov.:

AF XY:

0.859

AC XY:

64010

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.961

AC:

39951

AN:

41586

American (AMR)

AF:

0.835

AC:

12791

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.749

AC:

2599

AN:

3470

East Asian (EAS)

AF:

0.908

AC:

4685

AN:

5162

South Asian (SAS)

AF:

0.822

AC:

3968

AN:

4826

European-Finnish (FIN)

AF:

0.875

AC:

9303

AN:

10628

Middle Eastern (MID)

AF:

0.701

AC:

206

AN:

294

European-Non Finnish (NFE)

AF:

0.801

AC:

54491

AN:

68004

Other (OTH)

AF:

0.828

AC:

1750

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

993

1987

2980

3974

4967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.810

Hom.:

72680

Bravo

AF:

0.858

Asia WGS

AF:

0.840

AC:

2920

AN:

3478

EpiCase

AF:

0.786

EpiControl

AF:

0.790

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 31, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.8

(source)

DANN

Benign

0.58

PhyloP100

0.80

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over