chr2-165901737-G-A

Variant names:

• chr2-165901737-G-A
• rs73018799
• NM_024753.5:c.2742C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_024753.5(TTC21B):​c.2742C>T​(p.Cys914Cys) variant causes a synonymous change. The variant allele was found at a frequency of 0.00187 in 1,613,642 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (23 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.37
• Publications: 4 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-165901737-G-A is Benign according to our data. Variant chr2-165901737-G-A is described in ClinVar as Benign. ClinVar VariationId is 130654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00993 (1512/152194) while in subpopulation AFR AF = 0.034 (1410/41520). AF 95% confidence interval is 0.0325. There are 33 homozygotes in GnomAd4. There are 746 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.2742C>T	p.Cys914Cys	synonymous	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.2742C>T	p.Cys914Cys	synonymous	Exon 20 of 29	ENSP00000243344.7
	TTC21B	ENST00000679840.1		c.2742C>T	p.Cys914Cys	synonymous	Exon 20 of 27	ENSP00000505248.1
	TTC21B	ENST00000679799.1		c.2742C>T	p.Cys914Cys	synonymous	Exon 20 of 28	ENSP00000505208.1

Frequencies

GnomAD3 genomes AF: 0.00992 AC: 1509 AN: 152076 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00248 AC: 624 AN: 251234 AF XY: 0.00188

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00103 AC: 1501 AN: 1461448 Hom.: 23 Cov.: 32 AF XY: 0.000904 AC XY: 657 AN XY: 727044

African (AFR) AF: 0.0332 AC: 1112 AN: 33472

American (AMR) AF: 0.00221 AC: 99 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1111646

Other (OTH) AF: 0.00234 AC: 141 AN: 60376

GnomAD4 genome AF: 0.00993 AC: 1512 AN: 152194 Hom.: 33 Cov.: 32 AF XY: 0.0100 AC XY: 746 AN XY: 74410

African (AFR) AF: 0.0340 AC: 1410 AN: 41520

American (AMR) AF: 0.00471 AC: 72 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68016

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00861 Hom.: 10

Bravo AF: 0.0115

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Asphyxiating thoracic dystrophy 4 (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	-	1	Nephronophthisis 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.5
DANN	Benign	0.48
PhyloP100		4.4
Mutation Taster		=100/0	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: rs73018799; hg19: chr2-166758247;