rs886038205

Variant names:

• chr17-19343795-C-G
• rs886038205
• NM_015681.6:c.467G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-19343795-C-G
• chr17-19343795-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_015681.6(B9D1):​c.467G>C​(p.Arg156Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: B9D1 NM_015681.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.90
• Publications: 1 publications found

Genes affected

B9D1 (HGNC:24123): (B9 domain containing 1) This gene encodes a B9 domain-containing protein, one of several that are involved in ciliogenesis. Alterations in expression of this gene have been found in a family with Meckel syndrome. Meckel syndrome has been associated with at least six different genes. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Mar 2016]

B9D1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 27

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Meckel syndrome, type 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-19343795-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254678.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 17-19343795-C-G is Pathogenic according to our data. Variant chr17-19343795-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 558747.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015681.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	NM_015681.6	MANE Select	c.467G>C	p.Arg156Pro	missense	Exon 6 of 7	NP_056496.1
	B9D1	NM_001321214.2		c.467G>C	p.Arg156Pro	missense	Exon 6 of 7	NP_001308143.1
	B9D1	NM_001321217.2		c.467G>C	p.Arg156Pro	missense	Exon 6 of 7	NP_001308146.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	ENST00000261499.11	TSL:1 MANE Select	c.467G>C	p.Arg156Pro	missense	Exon 6 of 7	ENSP00000261499.4
	B9D1	ENST00000663089.1		c.530G>C	p.Arg177Pro	missense	Exon 7 of 7	ENSP00000499469.1
	B9D1	ENST00000395616.7	TSL:3	c.467G>C	p.Arg156Pro	missense	Exon 6 of 7	ENSP00000378978.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Dec 04, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jeune thoracic dystrophy Uncertain:1

May 01, 2018

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.76	D
PhyloP100		6.9
PrimateAI	Benign	0.39	T
Sift4G	Pathogenic	0.0	D
Vest4		0.60
MVP		0.68
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
Mutation Taster		=17/83	disease causing (ClinVar)

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: rs886038205; hg19: chr17-19247108;