2-165874238-C-T

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: 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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.*517G>A		3_prime_UTR_variant	Exon 29 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_047445870.1	c.*517G>A		3_prime_UTR_variant	Exon 25 of 25		XP_047301826.1
TTC21B	XM_011511871.4	c.*517G>A		3_prime_UTR_variant	Exon 24 of 24		XP_011510173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.*517G>A		3_prime_UTR_variant	Exon 29 of 29	1	NM_024753.5	ENSP00000243344.7

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Asphyxiating thoracic dystrophy 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis 12 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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;