2-219055217-G-A

Position:

• chr2-219055217-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002181.4(IHH):​c.1226C>T​(p.Ala409Val) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15617815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IHH	NM_002181.4	c.1226C>T	p.Ala409Val	missense_variant	3/3	ENST00000295731.7	NP_002172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IHH	ENST00000295731.7	c.1226C>T	p.Ala409Val	missense_variant	3/3	1	NM_002181.4	ENSP00000295731.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.1226C>T (p.A409V) alteration is located in exon 3 (coding exon 3) of the IHH gene. This alteration results from a C to T substitution at nucleotide position 1226, causing the alanine (A) at amino acid position 409 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.16	T
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.30
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.16		Loss of phosphorylation at S407 (P = 0.1665);
MVP		0.87
MPC		0.21
ClinPred		0.058	T
GERP RS		2.6
Varity_R		0.040
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-219919939;