15-82849827-C-A

Variant names:

• chr15-82849827-C-A
• rs376015771
• NM_004839.4:c.920G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004839.4(HOMER2):​c.920G>T​(p.Arg307Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOMER2 NM_004839.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 0 publications found

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]

HOMER2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 68

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33846262).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004839.4. 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
	HOMER2	NM_004839.4	MANE Select	c.920G>T	p.Arg307Leu	missense	Exon 9 of 9	NP_004830.2
	HOMER2	NM_199330.3		c.953G>T	p.Arg318Leu	missense	Exon 9 of 9	NP_955362.1	Q9NSB8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOMER2	ENST00000450735.7	TSL:1 MANE Select	c.920G>T	p.Arg307Leu	missense	Exon 9 of 9	ENSP00000407634.2	Q9NSB8-2
	HOMER2	ENST00000855505.1		c.983G>T	p.Arg328Leu	missense	Exon 10 of 10	ENSP00000525564.1
	HOMER2	ENST00000304231.12	TSL:5	c.953G>T	p.Arg318Leu	missense	Exon 9 of 9	ENSP00000305632.8	Q9NSB8-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.072
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.053	T
Polyphen		0.89	P
Vest4		0.43
MutPred		0.23		Loss of MoRF binding (P = 0.0415)
MVP		0.90
MPC		0.83
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		-0.015	Neutral
Varity_R		0.60
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376015771; hg19: chr15-83518579;