rs111033240

Variant names:

• chr7-107663331-C-G
• rs111033240
• NM_000441.2:c.200C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-107663331-C-G
• chr7-107663331-C-A
• chr7-107663331-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP2

This summary comes from the ClinGen Evidence Repository: The c.200C>G (p.Thr67Ser) variant in SLC26A4 is a missense variant predicted to cause substitution of threonine by serine at amino acid 67. The highest population minor allele frequency in gnomAD v4.0.0 is 4/39700 alleles (0.0001008 or 0.01 %) in the East Asian population (PM2_supporting, BS1, and BA1 not met). The results from two predictors/lines of evidence, MaxEntScan and conservation analysis, with serine present at this residue in ten vertebrates, suggest that the variant does not impact SLC26A4 function (BP4). This variant has been observed in cis with the variant p.Leu236Val (c.706C>G) [PMIDs: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6], which is classified as likely pathogenic by the ClinGen Hearing Loss VCEP, in at least six affected individuals (BP2). The variant has been seen in the homozygous and compound heterozygous (in trans, phase confirmed) state in at least three other individuals affected with hearing loss (PMIDs: 18250610, 22796198, 26969326). However, PM3 was not applied due to the fact that these individuals may also have carried the p.Leu236Val variant that was causative of the disorder. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Pendred Syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BP4, BP2; Version 2; 3/20/24). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132691/MONDO:0010134/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:1 B:5
• Conservation: PhyloP100: 0.651
• Publications: 5 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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

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.200C>G	p.Thr67Ser	missense	Exon 3 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.200C>G	p.Thr67Ser	missense	Exon 3 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.200C>G	p.Thr67Ser	missense	Exon 2 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.200C>G	p.Thr67Ser	missense	Exon 3 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251496 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	1	not provided (2)
-	-	2	not specified (2)
-	1	1	Pendred syndrome (2)
-	-	1	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	0.42
DANN	Benign	0.56
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.59	N
PhyloP100		0.65
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.2	N
REVEL	Uncertain	0.43
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.77		Loss of ubiquitination at K66 (P = 0.0992)
MVP		0.75
MPC		0.011
ClinPred		0.020	T
GERP RS		2.2
Varity_R		0.030
gMVP		0.36
Mutation Taster		=44/56	disease causing

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: rs111033240; hg19: chr7-107303776; COSMIC: COSV105848617; COSMIC: COSV105848617;