NM_033337.3:c.99C>T

Variant names:

• chr3-8733975-C-T
• rs1008642
• NM_033337.3:c.99C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_033337.3(CAV3):​c.99C>T​(p.Asn33Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,601,170 control chromosomes in the GnomAD database, including 60,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10596 hom., cov: 30)
  • Exomes 𝑓: 0.25 (49671 hom.)
• Consequence: CAV3 NM_033337.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: -0.522
• Publications: 35 publications found

Genes affected

CAV3 (HGNC:1529): (caveolin 3) This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]

SSUH2 (HGNC:24809): (ssu-2 homolog) Involved in odontogenesis. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SSUH2 Gene-Disease associations (from GenCC):

• dentin dysplasia type I

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 3-8733975-C-T is Benign according to our data. Variant chr3-8733975-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.522 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033337.3. 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
	CAV3	NM_033337.3	MANE Select	c.99C>T	p.Asn33Asn	synonymous	Exon 1 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.99C>T	p.Asn33Asn	synonymous	Exon 1 of 3	NP_001225.1	P56539

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	ENST00000343849.3	TSL:1 MANE Select	c.99C>T	p.Asn33Asn	synonymous	Exon 1 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.99C>T	p.Asn33Asn	synonymous	Exon 1 of 3	ENSP00000380525.2	P56539
	SSUH2	ENST00000478513.1	TSL:1	n.335+8484G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53036 AN: 151520 Hom.: 10583 Cov.: 30

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.294 AC: 73767 AN: 250794 AF XY: 0.284

Gnomad AFR exome AF: 0.560

Gnomad AMR exome AF: 0.323

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.397

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.294

GnomAD4 exome AF: 0.253 AC: 366328 AN: 1449532 Hom.: 49671 Cov.: 29 AF XY: 0.251 AC XY: 181175 AN XY: 721672

African (AFR) AF: 0.569 AC: 18839 AN: 33100

American (AMR) AF: 0.325 AC: 14535 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 7800 AN: 26070

East Asian (EAS) AF: 0.345 AC: 13669 AN: 39620

South Asian (SAS) AF: 0.210 AC: 18058 AN: 86036

European-Finnish (FIN) AF: 0.289 AC: 15442 AN: 53346

Middle Eastern (MID) AF: 0.326 AC: 1868 AN: 5734

European-Non Finnish (NFE) AF: 0.235 AC: 259179 AN: 1100994

Other (OTH) AF: 0.282 AC: 16938 AN: 59976

GnomAD4 genome AF: 0.350 AC: 53085 AN: 151638 Hom.: 10596 Cov.: 30 AF XY: 0.348 AC XY: 25812 AN XY: 74076

African (AFR) AF: 0.555 AC: 22941 AN: 41316

American (AMR) AF: 0.338 AC: 5151 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3470

East Asian (EAS) AF: 0.388 AC: 1989 AN: 5122

South Asian (SAS) AF: 0.213 AC: 1010 AN: 4752

European-Finnish (FIN) AF: 0.282 AC: 2969 AN: 10522

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16908 AN: 67914

Other (OTH) AF: 0.329 AC: 691 AN: 2098

Alfa AF: 0.282 Hom.: 14338

Bravo AF: 0.367

Asia WGS AF: 0.322 AC: 1121 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.257

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Caveolinopathy (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Limb-Girdle Muscular Dystrophy, Dominant (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.92
PhyloP100		-0.52
PromoterAI		-0.061	Neutral
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: rs1008642; hg19: chr3-8775661; COSMIC: COSV59561434;