Genetic Variant NM_014171.6:c.17-63A>G (chr2-46618710-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014171.6(CRIPT):c.17-63A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,047,444 control chromosomes in the GnomAD database, including 49,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6304 hom., cov: 32)

Exomes 𝑓: 0.30 ( 42748 hom. )

Consequence

CRIPT
NM_014171.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.08

Publications

21 publications found

Variant links:

Genes affected

CRIPT (HGNC:14312): (CXXC repeat containing interactor of PDZ3 domain) This gene encodes a protein that binds to the PDZ3 peptide recognition domain. The encoded protein may modulates protein interactions with the cytoskeleton. A mutation in this gene resulted in short stature with microcephaly and distinctive facies. [provided by RefSeq, Jun 2014]

CRIPT Gene-Disease associations (from GenCC):

Rothmund-Thomson syndrome, type 3
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

CRIPT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 2-46618710-A-G is Benign according to our data. Variant chr2-46618710-A-G is described in ClinVar as [Benign]. Clinvar id is 1259318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRIPT	NM_014171.6 link	c.17-63A>G		intron_variant	Intron 1 of 4	ENST00000238892.4	NP_054890.1	Q9P021

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRIPT	ENST00000238892.4 link	c.17-63A>G		intron_variant	Intron 1 of 4	1	NM_014171.6	ENSP00000238892.3		Q9P021

Frequencies

GnomAD3 genomes

AF:

0.279

AC:

42327

AN:

151954

Hom.:

6303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.440

Gnomad AMR

AF:

0.343

Gnomad ASJ

AF:

0.385

Gnomad EAS

AF:

0.105

Gnomad SAS

AF:

0.255

Gnomad FIN

AF:

0.273

Gnomad MID

AF:

0.283

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.282

GnomAD4 exome

AF:

0.302

AC:

270622

AN:

895372

Hom.:

42748

AF XY:

0.302

AC XY:

140953

AN XY:

466422

show subpopulations

African (AFR)

AF:

0.184

AC:

3838

AN:

20912

American (AMR)

AF:

0.369

AC:

12430

AN:

33712

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

7942

AN:

20340

East Asian (EAS)

AF:

0.0821

AC:

2902

AN:

35328

South Asian (SAS)

AF:

0.266

AC:

17570

AN:

65974

European-Finnish (FIN)

AF:

0.288

AC:

14743

AN:

51178

Middle Eastern (MID)

AF:

0.294

AC:

1193

AN:

4062

European-Non Finnish (NFE)

AF:

0.317

AC:

197586

AN:

622758

Other (OTH)

AF:

0.302

AC:

12418

AN:

41108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

8711

17422

26132

34843

43554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.278

AC:

42348

AN:

152072

Hom.:

6304

Cov.:

AF XY:

0.277

AC XY:

20567

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.193

AC:

8026

AN:

41500

American (AMR)

AF:

0.344

AC:

5249

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.385

AC:

1337

AN:

3470

East Asian (EAS)

AF:

0.105

AC:

543

AN:

5178

South Asian (SAS)

AF:

0.256

AC:

1229

AN:

4810

European-Finnish (FIN)

AF:

0.273

AC:

2883

AN:

10578

Middle Eastern (MID)

AF:

0.291

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.324

AC:

22009

AN:

67942

Other (OTH)

AF:

0.278

AC:

586

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1544

3088

4633

6177

7721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.308

Hom.:

31496

Bravo

AF:

0.275

Asia WGS

AF:

0.197

AC:

687

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 18, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.8

(source)

DANN

Benign

0.73

PhyloP100

2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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NM_014171.6:c.17-63A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over