rs191682790

Variant names:

• chr6-135429992-T-C
• rs191682790
• NM_001134831.2:c.2382A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001134831.2(AHI1):​c.2382A>G​(p.Lys794Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,530,120 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: AHI1 NM_001134831.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.986
• Publications: 0 publications found

Genes affected

AHI1 (HGNC:21575): (Abelson helper integration site 1) This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

AHI1 Gene-Disease associations (from GenCC):

• Joubert syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, ClinGen, Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.104).
• BP6: Variant 6-135429992-T-C is Benign according to our data. Variant chr6-135429992-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260846.
• BP7: Synonymous conserved (PhyloP=0.986 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134831.2. 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
	AHI1	NM_001134831.2	MANE Select	c.2382A>G	p.Lys794Lys	synonymous	Exon 18 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.2382A>G	p.Lys794Lys	synonymous	Exon 16 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.2382A>G	p.Lys794Lys	synonymous	Exon 18 of 29	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.2382A>G	p.Lys794Lys	synonymous	Exon 18 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.2382A>G	p.Lys794Lys	synonymous	Exon 16 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.2382A>G	p.Lys794Lys	synonymous	Exon 17 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151886 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000457

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000338 AC: 61 AN: 180344 AF XY: 0.000353

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000639

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000531

Gnomad OTH exome AF: 0.000833

GnomAD4 exome AF: 0.000532 AC: 733 AN: 1378116 Hom.: 0 Cov.: 23 AF XY: 0.000509 AC XY: 348 AN XY: 683402

African (AFR) AF: 0.000160 AC: 5 AN: 31266

American (AMR) AF: 0.000655 AC: 24 AN: 36666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24896

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38360

South Asian (SAS) AF: 0.00 AC: 0 AN: 75714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50000

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5482

European-Non Finnish (NFE) AF: 0.000627 AC: 664 AN: 1058370

Other (OTH) AF: 0.000662 AC: 38 AN: 57362

GnomAD4 genome AF: 0.000303 AC: 46 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74308

African (AFR) AF: 0.000168 AC: 7 AN: 41556

American (AMR) AF: 0.000328 AC: 5 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000457 AC: 31 AN: 67764

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000403 Hom.: 0

Bravo AF: 0.000408

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome (1)
-	1	-	Joubert syndrome 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.4
DANN	Benign	0.72
PhyloP100		0.99
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs191682790; hg19: chr6-135751130;