17-19343337-G-C

Variant names:

• chr17-19343337-G-C
• rs753785719
• NM_015681.6:c.597C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_015681.6(B9D1):​c.597C>G​(p.Pro199Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,052 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (1 hom.)
• Consequence: B9D1 NM_015681.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.21
• Publications: 0 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: G2P, Genomics England PanelApp
• Joubert syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-19343337-G-C is Benign according to our data. Variant chr17-19343337-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 388102.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000752 (110/1461844) while in subpopulation AMR AF = 0.00188 (84/44720). AF 95% confidence interval is 0.00155. There are 1 homozygotes in GnomAdExome4. There are 51 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	NM_015681.6	MANE Select	c.597C>G	p.Pro199Pro	synonymous	Exon 7 of 7	NP_056496.1	Q9UPM9-1
	B9D1	NM_001321214.2		c.*122C>G		3_prime_UTR	Exon 7 of 7	NP_001308143.1	A8MYG7
	B9D1	NM_001321215.3		c.*373C>G		3_prime_UTR	Exon 6 of 6	NP_001308144.1	A0A2R8Y646

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	ENST00000261499.11	TSL:1 MANE Select	c.597C>G	p.Pro199Pro	synonymous	Exon 7 of 7	ENSP00000261499.4	Q9UPM9-1
	B9D1	ENST00000642870.2		c.237C>G	p.Pro79Pro	synonymous	Exon 7 of 7	ENSP00000496409.2	A0A2R8Y822
	B9D1	ENST00000663089.1		c.*373C>G		3_prime_UTR	Exon 7 of 7	ENSP00000499469.1	A0A590UJK9

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000374 AC: 94 AN: 251388 AF XY: 0.000287

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.0000752 AC: 110 AN: 1461844 Hom.: 1 Cov.: 29 AF XY: 0.0000701 AC XY: 51 AN XY: 727226

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00188 AC: 84 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111996

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74360

African (AFR) AF: 0.0000483 AC: 2 AN: 41444

American (AMR) AF: 0.000392 AC: 6 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000110

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Meckel syndrome, type 9 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.42
DANN	Benign	0.54
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs753785719; hg19: chr17-19246650;