3-49256282-C-T

Position:

• chr3-49256282-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001135197.2(IHO1):​c.785C>T​(p.Ser262Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IHO1 NM_001135197.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.424

Genes affected

IHO1 (HGNC:27945): (interactor of HORMAD1 1) Predicted to be involved in gamete generation; meiosis I cell cycle process; and regulation of homologous chromosome segregation. Predicted to be active in condensed nuclear chromosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059926808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IHO1	NM_001135197.2	c.785C>T	p.Ser262Leu	missense_variant	8/8	ENST00000452691.7	NP_001128669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IHO1	ENST00000452691.7	c.785C>T	p.Ser262Leu	missense_variant	8/8	2	NM_001135197.2	ENSP00000407837.2
IHO1	ENST00000296449.9	c.785C>T	p.Ser262Leu	missense_variant	10/10	1		ENSP00000296449.5
IHO1	ENST00000438782.5	c.785C>T	p.Ser262Leu	missense_variant	8/8	5		ENSP00000391788.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2022

The c.785C>T (p.S262L) alteration is located in exon 10 (coding exon 7) of the CCDC36 gene. This alteration results from a C to T substitution at nucleotide position 785, causing the serine (S) at amino acid position 262 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.61	.;T;.
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Benign	0.014
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.094
MutPred		0.29		Loss of disorder (P = 0.0496);Loss of disorder (P = 0.0496);Loss of disorder (P = 0.0496);
MVP		0.068
MPC		0.21
ClinPred		0.055	T
GERP RS		0.37
Varity_R		0.11
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs2046820621; hg19: chr3-49293715;