rs767255075

Variant names:

• chr7-107700161-T-G
• rs767255075
• NM_000441.2:c.1693T>G
• SLC26A4 p.Cys565Gly

Your query was ambiguous. Multiple possible variants found:

• chr7-107700161-T-G
• chr7-107700161-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_000441.2(SLC26A4):​c.1693T>G​(p.Cys565Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,390,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C565Y) has been classified as Likely pathogenic. The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.69
• Publications: 2 publications found

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

SLC26A4 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107700162-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 43519.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.
• PP5: Variant 7-107700161-T-G is Pathogenic according to our data. Variant chr7-107700161-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 373978.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. 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
	SLC26A4	NM_000441.2	MANE Select	c.1693T>G	p.Cys565Gly	missense	Exon 15 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1693T>G	p.Cys565Gly	missense	Exon 15 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1693T>G	p.Cys565Gly	missense	Exon 14 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1615T>G	p.Cys539Gly	missense	Exon 14 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250542 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1390770 Hom.: 0 Cov.: 23 AF XY: 0.00000287 AC XY: 2 AN XY: 696422

African (AFR) AF: 0.00 AC: 0 AN: 32080

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 39352

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047170

Other (OTH) AF: 0.00 AC: 0 AN: 57992

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hearing impairment (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Benign	0.78
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.49	N
PhyloP100		2.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.58	N
REVEL	Uncertain	0.38
Sift	Benign	0.25	T
Sift4G	Benign	0.51	T
Varity_R		0.16
gMVP		0.61
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs767255075;

hg19: chr7-107340606;