rs2140412927

Variant names:

• chr15-67254920-C-A
• rs2140412927
• NM_001031715.3:c.24C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-67254920-C-A
• chr15-67254920-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001031715.3(IQCH):​c.24C>A​(p.His8Gln) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IQCH NM_001031715.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.617
• Publications: 0 publications found

Genes affected

IQCH (HGNC:25721): (IQ motif containing H)

AAGAB (HGNC:25662): (alpha and gamma adaptin binding protein) The protein encoded by this gene interacts with the gamma-adaptin and alpha-adaptin subunits of complexes involved in clathrin-coated vesicle trafficking. Mutations in this gene are associated with type I punctate palmoplantar keratoderma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

AAGAB Gene-Disease associations (from GenCC):

• palmoplantar keratoderma, punctate type 1A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• punctate palmoplantar keratoderma type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02473867).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031715.3. 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
	IQCH	NM_001031715.3	MANE Select	c.24C>A	p.His8Gln	missense	Exon 1 of 21	NP_001026885.2	Q86VS3-1
	IQCH	NM_022784.3		c.24C>A	p.His8Gln	missense	Exon 1 of 6	NP_073621.2	Q86VS3-5
	IQCH	NM_001322475.2		c.-280C>A		5_prime_UTR	Exon 1 of 18	NP_001309404.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQCH	ENST00000335894.9	TSL:1 MANE Select	c.24C>A	p.His8Gln	missense	Exon 1 of 21	ENSP00000336861.4	Q86VS3-1
	IQCH	ENST00000629425.2	TSL:1	c.-162C>A		5_prime_UTR	Exon 1 of 7	ENSP00000486970.1	Q86VS3-3
	IQCH	ENST00000512104.5	TSL:2	c.24C>A	p.His8Gln	missense	Exon 1 of 6	ENSP00000427323.1	Q86VS3-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.85
DANN	Benign	0.76
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.62
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.043
Sift	Benign	0.38	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.11		Gain of solvent accessibility (P = 0.0338)
MVP		0.014
MPC		0.10
ClinPred		0.077	T
GERP RS		-2.0
PromoterAI		-0.098	Neutral
Varity_R		0.063
gMVP		0.042
Mutation Taster		=289/11	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: rs2140412927; hg19: chr15-67547258;