2-219055217-G-T

Variant names:

• chr2-219055217-G-T
• rs2062760768
• NM_002181.4:c.1226C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002181.4(IHH):​c.1226C>A​(p.Ala409Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A409V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IHH NM_002181.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.208
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• acrocapitofemoral dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.4539 (below the threshold of 3.09). Trascript score misZ: 1.9945 (below the threshold of 3.09). GenCC associations: The gene is linked to brachydactyly type A1, acrocapitofemoral dysplasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17272449).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHH	NM_002181.4	MANE Select	c.1226C>A	p.Ala409Glu	missense	Exon 3 of 3	NP_002172.2	Q14623

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHH	ENST00000295731.7	TSL:1 MANE Select	c.1226C>A	p.Ala409Glu	missense	Exon 3 of 3	ENSP00000295731.5	Q14623

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.17	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.81	L
PhyloP100		0.21
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.35
Sift	Benign	0.36	T
Sift4G	Benign	0.35	T
Polyphen		0.010	B
Vest4		0.088
MutPred		0.20		Gain of solvent accessibility (P = 0.0456)
MVP		0.86
MPC		0.25
ClinPred		0.042	T
GERP RS		2.6
Varity_R		0.076
gMVP		0.45
Mutation Taster		=90/10	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: rs2062760768; hg19: chr2-219919939;