rs77199262

Variant names:

• chr2-165874238-C-T
• rs77199262
• NM_024753.5:c.*517G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024753.5(TTC21B):​c.*517G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 151,938 control chromosomes in the GnomAD database, including 2,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2345 hom., cov: 32)
  • Exomes 𝑓: 0.16 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTC21B NM_024753.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.56
• Publications: 2 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: Labcorp Genetics (formerly Invitae), 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=-0.95).
• BP6: Variant 2-165874238-C-T is Benign according to our data. Variant chr2-165874238-C-T is described in ClinVar as Benign. ClinVar VariationId is 331811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	NM_024753.5	MANE Select	c.*517G>A		3_prime_UTR	Exon 29 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.*517G>A		3_prime_UTR	Exon 29 of 29	ENSP00000243344.7	Q7Z4L5-1
	TTC21B	ENST00000959804.1		c.*517G>A		3_prime_UTR	Exon 28 of 28	ENSP00000629863.1
	TTC21B	ENST00000679799.1		c.3806-3218G>A		intron	N/A	ENSP00000505208.1	A0A494C0N4

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26112 AN: 151820 Hom.: 2344 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.209

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.158 AC: 133 AN: 842 Hom.: 13 Cov.: 0 AF XY: 0.167 AC XY: 95 AN XY: 570

African (AFR) AF: 0.167 AC: 1 AN: 6

American (AMR) AF: 0.0667 AC: 2 AN: 30

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 2 AN: 4

East Asian (EAS) AF: 0.147 AC: 5 AN: 34

South Asian (SAS) AF: 0.107 AC: 3 AN: 28

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AF: 0.500 AC: 2 AN: 4

European-Non Finnish (NFE) AF: 0.160 AC: 113 AN: 706

Other (OTH) AF: 0.167 AC: 4 AN: 24

GnomAD4 genome AF: 0.172 AC: 26128 AN: 151938 Hom.: 2345 Cov.: 32 AF XY: 0.172 AC XY: 12749 AN XY: 74288

African (AFR) AF: 0.138 AC: 5739 AN: 41484

American (AMR) AF: 0.186 AC: 2829 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 944 AN: 3464

East Asian (EAS) AF: 0.144 AC: 740 AN: 5142

South Asian (SAS) AF: 0.241 AC: 1163 AN: 4822

European-Finnish (FIN) AF: 0.150 AC: 1580 AN: 10534

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12375 AN: 67938

Other (OTH) AF: 0.208 AC: 440 AN: 2112

Alfa AF: 0.172 Hom.: 275

Bravo AF: 0.175

Asia WGS AF: 0.185 AC: 643 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Asphyxiating thoracic dystrophy 4 (1)
-	-	1	Nephronophthisis 12 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.34
DANN	Benign	0.73
PhyloP100		-3.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs77199262; hg19: chr2-166730748;