NM_000441.2:c.2145G>T

Variant names:

• chr7-107710109-G-T
• rs397516427
• NM_000441.2:c.2145G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3_Strong PS3_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The c.2145G>T variant in SLC26A4 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 715 (p.Lys715Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06777% (95% CI of 29/30610) in the South Asian population (PM2_supporting, BS1, and BA1 not met). This variant has been observed in 3 probands with hearing loss in trans with another pathogenic or likely pathogenic variant (PM3_Strong; PMID:26969326, PMID:32417962, LMM unpublished data SCV000060131.6). At least one proband with this variant presented with clinical features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4; LMM unpublished data SCV000060131.6).This variant has been observed in several other cases where a second variant in SLC26A4 was not found (PMID:19509082, 19287372, 26188157, 32417962). Functional studies including fluorescence assays and chloride exchange experiments have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:19509082). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 08/22/23: PM3_Strong, PS3_Supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261425/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:12 U:2
• Conservation: PhyloP100: 0.812
• Publications: 8 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_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.2145G>T	p.Lys715Asn	missense	Exon 19 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.2145G>T	p.Lys715Asn	missense	Exon 19 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.2145G>T	p.Lys715Asn	missense	Exon 18 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.2067G>T	p.Lys689Asn	missense	Exon 18 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251292 AF XY: 0.000184

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: 0.0000507 AC: 74 AN: 1458468 Hom.: 0 Cov.: 28 AF XY: 0.0000703 AC XY: 51 AN XY: 725890

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108920

Other (OTH) AF: 0.0000664 AC: 4 AN: 60268

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	1	-	Pendred syndrome (4)
3	-	-	Autosomal recessive nonsyndromic hearing loss 4 (3)
1	1	-	not provided (2)
2	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (2)
1	-	-	Monogenic hearing loss (1)
1	-	-	Rare genetic deafness (1)
1	-	-	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.0018
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.080	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.81
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.35
Sift	Benign	0.25	T
Sift4G	Benign	0.13	T
Polyphen		0.022	B
Vest4		0.83
MutPred		0.78		Loss of methylation at K715 (P = 0.0126)
MVP		0.94
MPC		0.018
ClinPred		0.92	D
GERP RS		2.7
Varity_R		0.24
gMVP		0.61
Mutation Taster		=16/84	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: rs397516427; hg19: chr7-107350554;