NM_024753.5:c.2175T>C

Variant names:

• chr2-165913610-A-G
• rs10176588
• NM_024753.5:c.2175T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024753.5(TTC21B):​c.2175T>C​(p.Phe725Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,609,282 control chromosomes in the GnomAD database, including 111,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8652 hom., cov: 32)
  • Exomes 𝑓: 0.37 (102902 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.130
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-165913610-A-G is Benign according to our data. Variant chr2-165913610-A-G is described in ClinVar as Benign. ClinVar VariationId is 130652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	NM_024753.5	MANE Select	c.2175T>C	p.Phe725Phe	synonymous	Exon 16 of 29	NP_079029.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.2175T>C	p.Phe725Phe	synonymous	Exon 16 of 29	ENSP00000243344.7
	TTC21B	ENST00000679840.1		c.2175T>C	p.Phe725Phe	synonymous	Exon 16 of 27	ENSP00000505248.1
	TTC21B	ENST00000679799.1		c.2175T>C	p.Phe725Phe	synonymous	Exon 16 of 28	ENSP00000505208.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50317 AN: 151786 Hom.: 8653 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.334

GnomAD2 exomes AF: 0.325 AC: 81315 AN: 250544 AF XY: 0.331

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.371 AC: 540297 AN: 1457378 Hom.: 102902 Cov.: 33 AF XY: 0.370 AC XY: 268180 AN XY: 725274

African (AFR) AF: 0.263 AC: 8767 AN: 33382

American (AMR) AF: 0.220 AC: 9812 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 10685 AN: 26088

East Asian (EAS) AF: 0.194 AC: 7695 AN: 39598

South Asian (SAS) AF: 0.334 AC: 28793 AN: 86158

European-Finnish (FIN) AF: 0.332 AC: 17679 AN: 53310

Middle Eastern (MID) AF: 0.285 AC: 1642 AN: 5758

European-Non Finnish (NFE) AF: 0.391 AC: 433036 AN: 1108146

Other (OTH) AF: 0.368 AC: 22188 AN: 60240

GnomAD4 genome AF: 0.331 AC: 50326 AN: 151904 Hom.: 8652 Cov.: 32 AF XY: 0.327 AC XY: 24290 AN XY: 74270

African (AFR) AF: 0.269 AC: 11127 AN: 41412

American (AMR) AF: 0.270 AC: 4128 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1437 AN: 3472

East Asian (EAS) AF: 0.195 AC: 1005 AN: 5166

South Asian (SAS) AF: 0.325 AC: 1563 AN: 4812

European-Finnish (FIN) AF: 0.334 AC: 3517 AN: 10518

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.388 AC: 26363 AN: 67942

Other (OTH) AF: 0.338 AC: 713 AN: 2112

Alfa AF: 0.359 Hom.: 29233

Bravo AF: 0.321

Asia WGS AF: 0.280 AC: 972 AN: 3474

EpiCase AF: 0.392

EpiControl AF: 0.384

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Asphyxiating thoracic dystrophy 4 (2)
-	-	1	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	-	1	Nephronophthisis 12 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.2
DANN	Benign	0.57
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs10176588; hg19: chr2-166770120; COSMIC: COSV54627817;