NM_001134831.2:c.2488C>T

Variant names:

• chr6-135429886-G-A
• rs13312995
• NM_001134831.2:c.2488C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134831.2(AHI1):​c.2488C>T​(p.Arg830Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,524,050 control chromosomes in the GnomAD database, including 484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R830Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (40 hom., cov: 32)
  • Exomes 𝑓: 0.024 (444 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.29
• Publications: 29 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008873045).
• BP6: Variant 6-135429886-G-A is Benign according to our data. Variant chr6-135429886-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0201 (3051/151600) while in subpopulation NFE AF = 0.0277 (1872/67678). AF 95% confidence interval is 0.0266. There are 40 homozygotes in GnomAd4. There are 1467 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR,AD gene

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.2488C>T	p.Arg830Trp	missense	Exon 18 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.2488C>T	p.Arg830Trp	missense	Exon 16 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.2488C>T	p.Arg830Trp	missense	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.2488C>T	p.Arg830Trp	missense	Exon 18 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.2488C>T	p.Arg830Trp	missense	Exon 16 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.2488C>T	p.Arg830Trp	missense	Exon 17 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3049 AN: 151484 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0359

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00810

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0236

GnomAD2 exomes AF: 0.0201 AC: 4173 AN: 207212 AF XY: 0.0204

Gnomad AFR exome AF: 0.00599

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0360

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0240

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0242 AC: 33229 AN: 1372450 Hom.: 444 Cov.: 23 AF XY: 0.0240 AC XY: 16341 AN XY: 682210

African (AFR) AF: 0.00475 AC: 151 AN: 31816

American (AMR) AF: 0.0185 AC: 750 AN: 40502

Ashkenazi Jewish (ASJ) AF: 0.0371 AC: 932 AN: 25094

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38634

South Asian (SAS) AF: 0.0104 AC: 820 AN: 78566

European-Finnish (FIN) AF: 0.0236 AC: 1204 AN: 51038

Middle Eastern (MID) AF: 0.0355 AC: 198 AN: 5584

European-Non Finnish (NFE) AF: 0.0267 AC: 27828 AN: 1043824

Other (OTH) AF: 0.0234 AC: 1345 AN: 57392

GnomAD4 genome AF: 0.0201 AC: 3051 AN: 151600 Hom.: 40 Cov.: 32 AF XY: 0.0198 AC XY: 1467 AN XY: 74086

African (AFR) AF: 0.00611 AC: 253 AN: 41418

American (AMR) AF: 0.0251 AC: 382 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 124 AN: 3456

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00811 AC: 39 AN: 4810

European-Finnish (FIN) AF: 0.0250 AC: 263 AN: 10534

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0277 AC: 1872 AN: 67678

Other (OTH) AF: 0.0233 AC: 49 AN: 2100

Alfa AF: 0.0251 Hom.: 189

Bravo AF: 0.0198

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.00608 AC: 22

ESP6500EA AF: 0.0263 AC: 214

ExAC AF: 0.0178 AC: 2135

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 1 (1)
-	-	1	Joubert syndrome 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.33
MPC		0.30
ClinPred		0.033	T
GERP RS		4.0
Varity_R		0.58
gMVP		0.75
Mutation Taster		=89/11	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: rs13312995; hg19: chr6-135751024;