chr2-165917461-G-A

Variant names:

• chr2-165917461-G-A
• rs6750044
• NM_024753.5:c.1695C>T

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.1695C>T​(p.Tyr565Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,610,158 control chromosomes in the GnomAD database, including 112,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9205 hom., cov: 32)
  • Exomes 𝑓: 0.37 (103351 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.08
• Publications: 20 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=-0.51).
• BP6: Variant 2-165917461-G-A is Benign according to our data. Variant chr2-165917461-G-A is described in ClinVar as Benign. ClinVar VariationId is 130650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.08 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.1695C>T	p.Tyr565Tyr	synonymous	Exon 14 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.1695C>T	p.Tyr565Tyr	synonymous	Exon 14 of 29	ENSP00000243344.7
	TTC21B	ENST00000679840.1		c.1695C>T	p.Tyr565Tyr	synonymous	Exon 14 of 27	ENSP00000505248.1
	TTC21B	ENST00000679799.1		c.1695C>T	p.Tyr565Tyr	synonymous	Exon 14 of 28	ENSP00000505208.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52206 AN: 151864 Hom.: 9205 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.342

GnomAD2 exomes AF: 0.328 AC: 82165 AN: 250882 AF XY: 0.333

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.326

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.372 AC: 542382 AN: 1458176 Hom.: 103351 Cov.: 34 AF XY: 0.371 AC XY: 269032 AN XY: 725616

African (AFR) AF: 0.304 AC: 10152 AN: 33416

American (AMR) AF: 0.222 AC: 9939 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 10694 AN: 26102

East Asian (EAS) AF: 0.194 AC: 7708 AN: 39656

South Asian (SAS) AF: 0.334 AC: 28810 AN: 86192

European-Finnish (FIN) AF: 0.332 AC: 17710 AN: 53380

Middle Eastern (MID) AF: 0.289 AC: 1577 AN: 5458

European-Non Finnish (NFE) AF: 0.391 AC: 433445 AN: 1109042

Other (OTH) AF: 0.371 AC: 22347 AN: 60214

GnomAD4 genome AF: 0.344 AC: 52224 AN: 151982 Hom.: 9205 Cov.: 32 AF XY: 0.338 AC XY: 25155 AN XY: 74316

African (AFR) AF: 0.312 AC: 12901 AN: 41412

American (AMR) AF: 0.276 AC: 4210 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1437 AN: 3470

East Asian (EAS) AF: 0.194 AC: 1005 AN: 5168

South Asian (SAS) AF: 0.326 AC: 1569 AN: 4820

European-Finnish (FIN) AF: 0.334 AC: 3528 AN: 10556

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.388 AC: 26373 AN: 67964

Other (OTH) AF: 0.345 AC: 727 AN: 2108

Alfa AF: 0.363 Hom.: 18382

Bravo AF: 0.335

Asia WGS AF: 0.284 AC: 988 AN: 3478

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	-0.51
CADD	Benign	6.6
DANN	Benign	0.44
PhyloP100		2.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6750044; hg19: chr2-166773971; COSMIC: COSV54627832;