rs182221

Variant names:

• chr16-56565309-C-G
• rs182221
• NM_032935.3:c.31+150C>G

Variant summary

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

The NM_032935.3(MT4):​c.31+150C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 672,270 control chromosomes in the GnomAD database, including 187,206 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 0.65 (35849 hom., cov: 32)
  • Exomes 𝑓: 0.76 (151357 hom.)
• Consequence: MT4 NM_032935.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.501
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT4	NM_032935.3	c.31+150C>G		intron_variant	Intron 1 of 2	ENST00000219162.4	NP_116324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT4	ENST00000219162.4	c.31+150C>G		intron_variant	Intron 1 of 2	1	NM_032935.3	ENSP00000219162.3
BBS2	ENST00000682930.1	c.42+5366G>C		intron_variant	Intron 2 of 18			ENSP00000507981.1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99382 AN: 152002 Hom.: 35849 Cov.: 32

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.790

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.784

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.683

GnomAD4 exome AF: 0.756 AC: 393018 AN: 520150 Hom.: 151357 AF XY: 0.754 AC XY: 203918 AN XY: 270400

African (AFR) AF: 0.318 AC: 3755 AN: 11794

American (AMR) AF: 0.816 AC: 10662 AN: 13072

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 9211 AN: 13676

East Asian (EAS) AF: 0.571 AC: 15139 AN: 26510

South Asian (SAS) AF: 0.687 AC: 29268 AN: 42632

European-Finnish (FIN) AF: 0.780 AC: 31821 AN: 40800

Middle Eastern (MID) AF: 0.678 AC: 2468 AN: 3642

European-Non Finnish (NFE) AF: 0.795 AC: 270453 AN: 340288

Other (OTH) AF: 0.730 AC: 20241 AN: 27736

GnomAD4 genome AF: 0.653 AC: 99406 AN: 152120 Hom.: 35849 Cov.: 32 AF XY: 0.654 AC XY: 48610 AN XY: 74372

African (AFR) AF: 0.330 AC: 13698 AN: 41488

American (AMR) AF: 0.790 AC: 12099 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 2367 AN: 3472

East Asian (EAS) AF: 0.574 AC: 2947 AN: 5132

South Asian (SAS) AF: 0.675 AC: 3260 AN: 4832

European-Finnish (FIN) AF: 0.784 AC: 8317 AN: 10604

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.799 AC: 54273 AN: 67968

Other (OTH) AF: 0.681 AC: 1437 AN: 2110

Alfa AF: 0.711 Hom.: 5081

Bravo AF: 0.641

Asia WGS AF: 0.592 AC: 2060 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.46
PhyloP100		-0.50
PromoterAI		-0.041	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: rs182221; hg19: chr16-56599221;