chr16-56568704-T-C

Variant names:

• chr16-56568704-T-C
• rs396230
• NM_032935.3:c.98-137T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032935.3(MT4):​c.98-137T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 581,374 control chromosomes in the GnomAD database, including 11,929 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3838 hom., cov: 30)
  • Exomes 𝑓: 0.19 (8091 hom.)
• Consequence: MT4 NM_032935.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.403
• Publications: 7 publications found

Genes affected

MT4 (HGNC:18705): (metallothionein 4) Predicted to enable metal ion binding activity. Predicted to be involved in cellular response to metal ion; cellular zinc ion homeostasis; and detoxification of copper ion. Predicted to act upstream of or within cellular metal ion homeostasis. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

BBS2 (HGNC:967): (Bardet-Biedl syndrome 2) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene forms a multiprotein BBSome complex with seven other BBS proteins.[provided by RefSeq, Oct 2014]

BBS2 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 74

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT4	NM_032935.3	c.98-137T>C		intron_variant	Intron 2 of 2	ENST00000219162.4	NP_116324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT4	ENST00000219162.4	c.98-137T>C		intron_variant	Intron 2 of 2	1	NM_032935.3	ENSP00000219162.3
BBS2	ENST00000682930.1	c.42+1971A>G		intron_variant	Intron 2 of 18			ENSP00000507981.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32235 AN: 151876 Hom.: 3839 Cov.: 30

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0938

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.187 AC: 80184 AN: 429378 Hom.: 8091 AF XY: 0.188 AC XY: 42467 AN XY: 226296

African (AFR) AF: 0.327 AC: 3752 AN: 11462

American (AMR) AF: 0.156 AC: 3174 AN: 20348

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 1211 AN: 11928

East Asian (EAS) AF: 0.274 AC: 7960 AN: 29054

South Asian (SAS) AF: 0.253 AC: 7008 AN: 27666

European-Finnish (FIN) AF: 0.174 AC: 6310 AN: 36166

Middle Eastern (MID) AF: 0.201 AC: 410 AN: 2036

European-Non Finnish (NFE) AF: 0.172 AC: 45798 AN: 266790

Other (OTH) AF: 0.191 AC: 4561 AN: 23928

GnomAD4 genome AF: 0.212 AC: 32279 AN: 151996 Hom.: 3838 Cov.: 30 AF XY: 0.213 AC XY: 15834 AN XY: 74284

African (AFR) AF: 0.323 AC: 13395 AN: 41440

American (AMR) AF: 0.175 AC: 2670 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0938 AC: 325 AN: 3466

East Asian (EAS) AF: 0.265 AC: 1364 AN: 5152

South Asian (SAS) AF: 0.235 AC: 1128 AN: 4802

European-Finnish (FIN) AF: 0.169 AC: 1787 AN: 10584

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11095 AN: 67978

Other (OTH) AF: 0.193 AC: 407 AN: 2108

Alfa AF: 0.179 Hom.: 3837

Bravo AF: 0.217

Asia WGS AF: 0.264 AC: 918 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.9
DANN	Benign	0.75
PhyloP100		0.40
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: rs396230; hg19: chr16-56602616; COSMIC: COSV54642393;