NM_175875.5:c.2192T>C

Variant names:

• chr19-45765529-A-G
• rs201416246
• NM_175875.5:c.2192T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_175875.5(SIX5):​c.2192T>C​(p.Val731Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,286 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V731V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.29
• Publications: 0 publications found

Genes affected

SIX5 (HGNC:10891): (SIX homeobox 5) The protein encoded by this gene is a homeodomain-containing transcription factor that appears to function in the regulation of organogenesis. This gene is located downstream of the dystrophia myotonica-protein kinase gene. Mutations in this gene are a cause of branchiootorenal syndrome type 2. [provided by RefSeq, Jul 2009]

SIX5 Gene-Disease associations (from GenCC):

• branchiootorenal syndrome 2

  Inheritance: Unknown, AD Classification: DEFINITIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• branchio-oto-renal syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet

ENSG00000259605 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175875.5. 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
	SIX5	NM_175875.5	MANE Select	c.2192T>C	p.Val731Ala	missense	Exon 3 of 3	NP_787071.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX5	ENST00000317578.7	TSL:1 MANE Select	c.2192T>C	p.Val731Ala	missense	Exon 3 of 3	ENSP00000316842.4	Q8N196
	SIX5	ENST00000560160.1	TSL:2	c.*402T>C		3_prime_UTR	Exon 2 of 2	ENSP00000453239.2	H0YLK1
	SIX5	ENST00000560168.1	TSL:4	c.*1618T>C		3_prime_UTR	Exon 3 of 3	ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251222 AF XY: 0.00000736

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461112 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 726894

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Branchiootorenal syndrome 2 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	0.69	N
PhyloP100		7.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.099		Loss of stability (P = 0.0446)
MVP		0.93
MPC		0.32
ClinPred		0.86	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.41
Mutation Taster		=84/16	polymorphism

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: rs201416246; hg19: chr19-46268787;