15-82851175-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004839.4(HOMER2):c.819C>T(p.Cys273=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,578,498 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (7 hom., cov: 33)
  • Exomes 𝑓: 0.016 (175 hom.)
• Consequence: HOMER2 NM_004839.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.98

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-82851175-G-A is Benign according to our data. Variant chr15-82851175-G-A is described in ClinVar as [Benign]. Clinvar id is 508589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-82851175-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0106 (1619/152238) while in subpopulation NFE AF= 0.0159 (1082/68022). AF 95% confidence interval is 0.0151. There are 7 homozygotes in gnomad4. There are 761 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1619 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOMER2	NM_004839.4	c.819C>T	p.Cys273=	synonymous_variant	8/9	ENST00000450735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOMER2	ENST00000450735.7	c.819C>T	p.Cys273=	synonymous_variant	8/9	1	NM_004839.4
HOMER2	ENST00000304231.12	c.852C>T	p.Cys284=	synonymous_variant	8/9	5		P1
HOMER2	ENST00000558552.1	n.699C>T		non_coding_transcript_exon_variant	2/3	2
HOMER2	ENST00000558817.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1619 AN: 152120 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0103 AC: 2045 AN: 197600 Hom.: 11 AF XY: 0.0108 AC XY: 1141 AN XY: 105274

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.00584

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00614

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0158 AC: 22496 AN: 1426260 Hom.: 175 Cov.: 30 AF XY: 0.0157 AC XY: 11049 AN XY: 705810

Gnomad4 AFR exome AF: 0.00273

Gnomad4 AMR exome AF: 0.00694

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0000778

Gnomad4 SAS exome AF: 0.00619

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0106 AC: 1619 AN: 152238 Hom.: 7 Cov.: 33 AF XY: 0.0102 AC XY: 761 AN XY: 74420

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0145 Hom.: 25

Bravo AF: 0.0113

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

HOMER2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	8.8
Dann	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs74416301; hg19: chr15-83519927;