rs142565795

Variant names:

• chr2-165898670-A-G
• rs142565795
• NM_024753.5:c.2950+16T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024753.5(TTC21B):​c.2950+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000794 in 1,559,818 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (5 hom.)
• Consequence: TTC21B NM_024753.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.72
• Publications: 1 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):

• asphyxiating thoracic dystrophy 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nephronophthisis 12

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-165898670-A-G is Benign according to our data. Variant chr2-165898670-A-G is described in ClinVar as Benign. ClinVar VariationId is 261778.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 = 0.00421 (641/152334) while in subpopulation AFR AF = 0.0149 (621/41566). AF 95% confidence interval is 0.014. There are 8 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.2950+16T>C		intron	N/A	NP_079029.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.2950+16T>C		intron	N/A	ENSP00000243344.7	Q7Z4L5-1
	TTC21B	ENST00000679840.1		c.2950+16T>C		intron	N/A	ENSP00000505248.1	A0A7P0T8P4
	TTC21B	ENST00000679799.1		c.2950+16T>C		intron	N/A	ENSP00000505208.1	A0A494C0N4

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 641 AN: 152216 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00115 AC: 289 AN: 250806 AF XY: 0.000804

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000424 AC: 597 AN: 1407484 Hom.: 5 Cov.: 25 AF XY: 0.000362 AC XY: 255 AN XY: 703556

African (AFR) AF: 0.0160 AC: 516 AN: 32336

American (AMR) AF: 0.000336 AC: 15 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 85172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5672

European-Non Finnish (NFE) AF: 0.0000179 AC: 19 AN: 1062478

Other (OTH) AF: 0.000751 AC: 44 AN: 58608

GnomAD4 genome AF: 0.00421 AC: 641 AN: 152334 Hom.: 8 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74494

African (AFR) AF: 0.0149 AC: 621 AN: 41566

American (AMR) AF: 0.000850 AC: 13 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00203 Hom.: 0

Bravo AF: 0.00481

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.57
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs142565795; hg19: chr2-166755180;