NM_001134831.2:c.2223T>C

Variant names:

• chr6-135433070-A-G
• rs2273761
• NM_001134831.2:c.2223T>C
• AHI1 p.Asp741Asp

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_001134831.2(AHI1):​c.2223T>C​(p.Asp741Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,613,536 control chromosomes in the GnomAD database, including 521 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (63 hom., cov: 32)
  • Exomes 𝑓: 0.021 (458 hom.)
• Consequence: AHI1 NM_001134831.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.00500
• Publications: 10 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: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• 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 -17 ACMG points.

• BP6: Variant 6-135433070-A-G is Benign according to our data. Variant chr6-135433070-A-G is described in ClinVar as Benign. ClinVar VariationId is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.005 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0243 (3703/152296) while in subpopulation EAS AF = 0.0542 (281/5186). AF 95% confidence interval is 0.049. There are 63 homozygotes in GnomAd4. There are 1839 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 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.2223T>C	p.Asp741Asp	synonymous	Exon 16 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.2223T>C	p.Asp741Asp	synonymous	Exon 14 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.2223T>C	p.Asp741Asp	synonymous	Exon 16 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.2223T>C	p.Asp741Asp	synonymous	Exon 16 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.2223T>C	p.Asp741Asp	synonymous	Exon 14 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.2223T>C	p.Asp741Asp	synonymous	Exon 15 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3696 AN: 152178 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0537

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0241 AC: 6006 AN: 248980 AF XY: 0.0248

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.00997

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.0629

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0208 AC: 30418 AN: 1461240 Hom.: 458 Cov.: 31 AF XY: 0.0215 AC XY: 15630 AN XY: 726938

African (AFR) AF: 0.0351 AC: 1173 AN: 33454

American (AMR) AF: 0.0110 AC: 492 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 493 AN: 26126

East Asian (EAS) AF: 0.0429 AC: 1699 AN: 39618

South Asian (SAS) AF: 0.0415 AC: 3582 AN: 86246

European-Finnish (FIN) AF: 0.0192 AC: 1023 AN: 53394

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5764

European-Non Finnish (NFE) AF: 0.0182 AC: 20255 AN: 1111566

Other (OTH) AF: 0.0267 AC: 1610 AN: 60354

GnomAD4 genome AF: 0.0243 AC: 3703 AN: 152296 Hom.: 63 Cov.: 32 AF XY: 0.0247 AC XY: 1839 AN XY: 74478

African (AFR) AF: 0.0362 AC: 1504 AN: 41556

American (AMR) AF: 0.0167 AC: 255 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.0542 AC: 281 AN: 5186

South Asian (SAS) AF: 0.0333 AC: 161 AN: 4830

European-Finnish (FIN) AF: 0.0208 AC: 221 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1172 AN: 68020

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.0202 Hom.: 75

Bravo AF: 0.0256

Asia WGS AF: 0.0450 AC: 157 AN: 3476

EpiCase AF: 0.0186

EpiControl AF: 0.0186

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.2
DANN	Benign	0.42
PhyloP100		0.0050
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2273761;

hg19: chr6-135754208;