rs2341097

Variant names:

• chr19-45765644-C-T
• rs2341097
• NM_175875.5:c.2077G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175875.5(SIX5):​c.2077G>A​(p.Val693Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,612,970 control chromosomes in the GnomAD database, including 97,361 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8345 hom., cov: 33)
  • Exomes 𝑓: 0.35 (89016 hom.)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0790
• Publications: 47 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041387975).
• BP6: Variant 19-45765644-C-T is Benign according to our data. Variant chr19-45765644-C-T is described in ClinVar as Benign. ClinVar VariationId is 262913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

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.2077G>A	p.Val693Met	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.2077G>A	p.Val693Met	missense	Exon 3 of 3	ENSP00000316842.4	Q8N196
	SIX5	ENST00000560160.1	TSL:2	c.*287G>A		3_prime_UTR	Exon 2 of 2	ENSP00000453239.2	H0YLK1
	SIX5	ENST00000560168.1	TSL:4	c.*1503G>A		3_prime_UTR	Exon 3 of 3	ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49969 AN: 151972 Hom.: 8344 Cov.: 33

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.320 AC: 79957 AN: 250156 AF XY: 0.323

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.284

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.345 AC: 504731 AN: 1460880 Hom.: 89016 Cov.: 60 AF XY: 0.345 AC XY: 251012 AN XY: 726800

African (AFR) AF: 0.308 AC: 10326 AN: 33478

American (AMR) AF: 0.218 AC: 9765 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 10929 AN: 26124

East Asian (EAS) AF: 0.218 AC: 8664 AN: 39698

South Asian (SAS) AF: 0.293 AC: 25281 AN: 86256

European-Finnish (FIN) AF: 0.314 AC: 16464 AN: 52498

Middle Eastern (MID) AF: 0.382 AC: 2201 AN: 5768

European-Non Finnish (NFE) AF: 0.360 AC: 399973 AN: 1111956

Other (OTH) AF: 0.350 AC: 21128 AN: 60384

GnomAD4 genome AF: 0.329 AC: 49984 AN: 152090 Hom.: 8345 Cov.: 33 AF XY: 0.323 AC XY: 24007 AN XY: 74368

African (AFR) AF: 0.313 AC: 12970 AN: 41466

American (AMR) AF: 0.262 AC: 4013 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3466

East Asian (EAS) AF: 0.266 AC: 1370 AN: 5158

South Asian (SAS) AF: 0.289 AC: 1393 AN: 4826

European-Finnish (FIN) AF: 0.319 AC: 3384 AN: 10592

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24361 AN: 67964

Other (OTH) AF: 0.316 AC: 668 AN: 2114

Alfa AF: 0.343 Hom.: 8388

Bravo AF: 0.323

TwinsUK AF: 0.362 AC: 1341

ALSPAC AF: 0.352 AC: 1355

ESP6500AA AF: 0.305 AC: 1342

ESP6500EA AF: 0.364 AC: 3127

ExAC AF: 0.319 AC: 38720

Asia WGS AF: 0.285 AC: 991 AN: 3478

EpiCase AF: 0.371

EpiControl AF: 0.375

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Branchiootorenal syndrome 2 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.079
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.23
Sift	Benign	0.032	D
Sift4G	Benign	0.10	T
Polyphen		0.63	P
Vest4		0.27
MPC		0.13
ClinPred		0.018	T
GERP RS		3.1
Varity_R		0.083
gMVP		0.067
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs2341097; hg19: chr19-46268902; COSMIC: COSV52177974; COSMIC: COSV52177974;