NM_002803.4:c.71-1283C>T

Variant names:

• chr7-103352638-C-T
• rs35850434
• NM_002803.4:c.71-1283C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002803.4(PSMC2):​c.71-1283C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 495,342 control chromosomes in the GnomAD database, including 10,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2633 hom., cov: 31)
  • Exomes 𝑓: 0.19 (7557 hom.)
• Consequence: PSMC2 NM_002803.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.379
• Publications: 1 publications found

Genes affected

PSMC2 (HGNC:9548): (proteasome 26S subunit, ATPase 2) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. This subunit has been shown to interact with several of the basal transcription factors so, in addition to participation in proteasome functions, this subunit may participate in the regulation of transcription. This subunit may also compete with PSMC3 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2011]

SLC26A5 (HGNC:9359): (solute carrier family 26 member 5) This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

SLC26A5 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 61

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 7-103352638-C-T is Benign according to our data. Variant chr7-103352638-C-T is described in ClinVar as Benign. ClinVar VariationId is 1249288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002803.4. 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
	PSMC2	NM_002803.4	MANE Select	c.71-1283C>T		intron	N/A	NP_002794.1	P35998-1
	PSMC2	NM_001204453.1		c.71-1283C>T		intron	N/A	NP_001191382.1	P35998
	SLC26A5	NM_206883.3		c.*272G>A		downstream_gene	N/A	NP_996766.1	P58743-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMC2	ENST00000292644.5	TSL:1 MANE Select	c.71-1283C>T		intron	N/A	ENSP00000292644.3	P35998-1
	PSMC2	ENST00000435765.5	TSL:5	c.71-1283C>T		intron	N/A	ENSP00000391211.1	P35998-1
	PSMC2	ENST00000678493.1		c.71-1283C>T		intron	N/A	ENSP00000502939.1	P35998-1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24809 AN: 151926 Hom.: 2635 Cov.: 31

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0887

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.191 AC: 65501 AN: 343298 Hom.: 7557 AF XY: 0.184 AC XY: 33886 AN XY: 184244

African (AFR) AF: 0.0483 AC: 471 AN: 9746

American (AMR) AF: 0.133 AC: 2046 AN: 15396

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 2310 AN: 10070

East Asian (EAS) AF: 0.000473 AC: 10 AN: 21152

South Asian (SAS) AF: 0.0869 AC: 3785 AN: 43554

European-Finnish (FIN) AF: 0.200 AC: 3878 AN: 19378

Middle Eastern (MID) AF: 0.198 AC: 277 AN: 1398

European-Non Finnish (NFE) AF: 0.241 AC: 49071 AN: 203380

Other (OTH) AF: 0.190 AC: 3653 AN: 19224

GnomAD4 genome AF: 0.163 AC: 24807 AN: 152044 Hom.: 2633 Cov.: 31 AF XY: 0.159 AC XY: 11827 AN XY: 74298

African (AFR) AF: 0.0491 AC: 2037 AN: 41500

American (AMR) AF: 0.161 AC: 2459 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 765 AN: 3466

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5182

South Asian (SAS) AF: 0.0896 AC: 432 AN: 4820

European-Finnish (FIN) AF: 0.187 AC: 1973 AN: 10546

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16543 AN: 67946

Other (OTH) AF: 0.181 AC: 380 AN: 2102

Alfa AF: 0.205 Hom.: 453

Bravo AF: 0.155

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.3
DANN	Benign	0.67
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs35850434; hg19: chr7-102993085;