2-165874224-T-C

Variant names:

• chr2-165874224-T-C
• rs56115495
• NM_024753.5:c.*531A>G

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.*531A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,046 control chromosomes in the GnomAD database, including 2,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2283 hom., cov: 32)
  • Exomes 𝑓: 0.16 (9 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: 0.638
• 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=-0.89).
• BP6: Variant 2-165874224-T-C is Benign according to our data. Variant chr2-165874224-T-C is described in ClinVar as [Benign]. Clinvar id is 331810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.*531A>G		3_prime_UTR_variant	Exon 29 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_047445870.1	c.*531A>G		3_prime_UTR_variant	Exon 25 of 25		XP_047301826.1
TTC21B	XM_011511871.4	c.*531A>G		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.*531A>G		3_prime_UTR_variant	Exon 29 of 29	1	NM_024753.5	ENSP00000243344.7

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25636 AN: 151928 Hom.: 2278 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.205

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.156 AC: 109 AN: 698 Hom.: 9 Cov.: 0 AF XY: 0.152 AC XY: 75 AN XY: 492

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.0357 AC: 1 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.125 AC: 5 AN: 40

South Asian (SAS) AF: 0.111 AC: 2 AN: 18

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.160 AC: 93 AN: 580

Other (OTH) AF: 0.200 AC: 4 AN: 20

GnomAD4 genome AF: 0.169 AC: 25657 AN: 152046 Hom.: 2283 Cov.: 32 AF XY: 0.168 AC XY: 12491 AN XY: 74332

African (AFR) AF: 0.139 AC: 5766 AN: 41496

American (AMR) AF: 0.184 AC: 2810 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3464

East Asian (EAS) AF: 0.128 AC: 661 AN: 5154

South Asian (SAS) AF: 0.219 AC: 1057 AN: 4822

European-Finnish (FIN) AF: 0.149 AC: 1574 AN: 10560

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12170 AN: 67966

Other (OTH) AF: 0.204 AC: 430 AN: 2110

Alfa AF: 0.170 Hom.: 264

Bravo AF: 0.172

Asia WGS AF: 0.166 AC: 577 AN: 3474

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	-0.89
CADD	Benign	4.3
DANN	Benign	0.73
PhyloP100		0.64
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: rs56115495; hg19: chr2-166730734;