2-19931423-C-A

Variant names:

• chr2-19931423-C-A
• rs1191779
• NM_001006657.2:c.2857-14G>T

Variant summary

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

The NM_020779.4(WDR35):​c.2824-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,612,746 control chromosomes in the GnomAD database, including 795,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71782 hom., cov: 31)
  • Exomes 𝑓: 1.0 (723524 hom.)
• Consequence: WDR35 NM_020779.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.09
• Publications: 6 publications found

Genes affected

WDR35 (HGNC:29250): (WD repeat domain 35) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. Two patients with Sensenbrenner syndrome / cranioectodermal dysplasia (CED) were identified with mutations in this gene, consistent with a possible ciliary function.[provided by RefSeq, Sep 2010]

WDR35 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P, Ambry Genetics
• short-rib thoracic dysplasia 7 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  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=-0.92).
• BP6: Variant 2-19931423-C-A is Benign according to our data. Variant chr2-19931423-C-A is described in ClinVar as Benign. ClinVar VariationId is 167846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020779.4. 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
	WDR35	NM_001006657.2	MANE Plus Clinical	c.2857-14G>T		intron	N/A	NP_001006658.1	Q9P2L0-1
	WDR35	NM_020779.4	MANE Select	c.2824-14G>T		intron	N/A	NP_065830.2	Q9P2L0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR35	ENST00000345530.8	TSL:1 MANE Plus Clinical	c.2857-14G>T		intron	N/A	ENSP00000314444.5	Q9P2L0-1
	WDR35	ENST00000281405.9	TSL:1 MANE Select	c.2824-14G>T		intron	N/A	ENSP00000281405.5	Q9P2L0-2
	WDR35	ENST00000968993.1		c.2752-14G>T		intron	N/A	ENSP00000639052.1

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147581 AN: 152112 Hom.: 71734 Cov.: 31

Gnomad AFR AF: 0.903

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.983

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.985

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.977

GnomAD2 exomes AF: 0.990 AC: 248082 AN: 250652 AF XY: 0.991

Gnomad AFR exome AF: 0.899

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 0.991

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.990

GnomAD4 exome AF: 0.995 AC: 1453574 AN: 1460518 Hom.: 723524 Cov.: 42 AF XY: 0.995 AC XY: 723044 AN XY: 726610

African (AFR) AF: 0.901 AC: 30137 AN: 33444

American (AMR) AF: 0.994 AC: 44420 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.991 AC: 25870 AN: 26100

East Asian (EAS) AF: 1.00 AC: 39529 AN: 39534

South Asian (SAS) AF: 0.986 AC: 84994 AN: 86222

European-Finnish (FIN) AF: 1.00 AC: 52898 AN: 52898

Middle Eastern (MID) AF: 0.974 AC: 5609 AN: 5758

European-Non Finnish (NFE) AF: 0.999 AC: 1110409 AN: 1111512

Other (OTH) AF: 0.989 AC: 59708 AN: 60344

GnomAD4 genome AF: 0.970 AC: 147686 AN: 152228 Hom.: 71782 Cov.: 31 AF XY: 0.971 AC XY: 72248 AN XY: 74430

African (AFR) AF: 0.903 AC: 37525 AN: 41540

American (AMR) AF: 0.984 AC: 15037 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 3430 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5178 AN: 5182

South Asian (SAS) AF: 0.985 AC: 4741 AN: 4812

European-Finnish (FIN) AF: 1.00 AC: 10605 AN: 10606

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67906 AN: 68012

Other (OTH) AF: 0.977 AC: 2062 AN: 2110

Alfa AF: 0.983 Hom.: 13907

Bravo AF: 0.966

Asia WGS AF: 0.984 AC: 3408 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Cranioectodermal dysplasia 2 (2)
-	-	2	Short-rib thoracic dysplasia 7 with or without polydactyly (2)
-	-	1	Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.047
DANN	Benign	0.30
PhyloP100		-1.1
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: rs1191779; hg19: chr2-20131184;