rs864309524

Positions:

• chr15-82854741-C-G
• chr15-82854741-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000450735.7(HOMER2):​c.554G>C​(p.Arg185Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOMER2 ENST00000450735.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.53

Genes affected

HOMER2 (HGNC:17513): (homer scaffold protein 2) This gene encodes a member of the homer family of dendritic proteins. Members of this family regulate group 1 metabotrophic glutamate receptor function. The encoded protein is a postsynaptic density scaffolding protein. Alternative splicing results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 14. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796
• PP5: Variant 15-82854741-C-G is Pathogenic according to our data. Variant chr15-82854741-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 218351.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-82854741-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOMER2	NM_004839.4	c.554G>C	p.Arg185Pro	missense_variant	6/9	ENST00000450735.7	NP_004830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOMER2	ENST00000450735.7	c.554G>C	p.Arg185Pro	missense_variant	6/9	1	NM_004839.4	ENSP00000407634
HOMER2	ENST00000304231.12	c.587G>C	p.Arg196Pro	missense_variant	6/9	5		ENSP00000305632	P1
HOMER2	ENST00000558817.1	c.311G>C	p.Arg104Pro	missense_variant	3/5	3		ENSP00000454125
HOMER2	ENST00000561345.5	n.613G>C		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 68 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.93
MutPred		0.34		.;Loss of methylation at R196 (P = 0.0183);.;
MVP		0.96
MPC		0.99
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.76

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: rs864309524; hg19: chr15-83523493;