rs34489989

Variant names:

• chr2-165901892-G-A
• rs34489989
• NM_024753.5:c.2587C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_024753.5(TTC21B):​c.2587C>T​(p.Arg863Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,613,102 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R863Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2 O:1
• Conservation: PhyloP100: 2.66
• Publications: 7 publications found

Genes affected

TTC21B (HGNC:25660): (tetratricopeptide repeat domain 21B) This gene encodes a member of TTC21 family, containing several tetratricopeptide repeat (TPR) domains. This protein is localized to the cilium axoneme, and may play a role in retrograde intraflagellar transport in cilia. Mutations in this gene are associated with various ciliopathies, nephronophthisis 12, and asphyxiating thoracic dystrophy 4. [provided by RefSeq, Oct 2011]

TTC21B Gene-Disease associations (from GenCC):

• nephronophthisis 12

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• asphyxiating thoracic dystrophy 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23543653).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024753.5. 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
	TTC21B	NM_024753.5	MANE Select	c.2587C>T	p.Arg863Trp	missense	Exon 20 of 29	NP_079029.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.2587C>T	p.Arg863Trp	missense	Exon 20 of 29	ENSP00000243344.7
	TTC21B	ENST00000679840.1		c.2587C>T	p.Arg863Trp	missense	Exon 20 of 27	ENSP00000505248.1
	TTC21B	ENST00000679799.1		c.2587C>T	p.Arg863Trp	missense	Exon 20 of 28	ENSP00000505208.1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 151302 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000290

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000816 AC: 205 AN: 251304 AF XY: 0.000832

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00188 AC: 2744 AN: 1461686 Hom.: 3 Cov.: 32 AF XY: 0.00183 AC XY: 1328 AN XY: 727152

African (AFR) AF: 0.000329 AC: 11 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00240 AC: 2663 AN: 1111886

Other (OTH) AF: 0.000828 AC: 50 AN: 60388

GnomAD4 genome AF: 0.00103 AC: 156 AN: 151416 Hom.: 0 Cov.: 32 AF XY: 0.000812 AC XY: 60 AN XY: 73890

African (AFR) AF: 0.000364 AC: 15 AN: 41202

American (AMR) AF: 0.000132 AC: 2 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.000290 AC: 3 AN: 10354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00199 AC: 135 AN: 67928

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.000982

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.00164

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	-	not provided (8)
-	2	-	Asphyxiating thoracic dystrophy 4 (2)
-	-	1	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	1	-	Nephronophthisis 12 (1)
-	-	1	TTC21B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.49
MPC		0.24
ClinPred		0.19	T
GERP RS		3.8
Varity_R		0.53
gMVP		0.50
Mutation Taster		=69/31	polymorphism

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: rs34489989; hg19: chr2-166758402; COSMIC: COSV99693093;