NM_016932.5:c.707C>T

Variant names:

• chr2-45006339-G-A
• rs372153489
• NM_016932.5:c.707C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016932.5(SIX2):​c.707C>T​(p.Pro236Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000307 in 1,613,892 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: SIX2 NM_016932.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.23
• Publications: 4 publications found

Genes affected

SIX2 (HGNC:10888): (SIX homeobox 2) This gene is a member of the vertebrate gene family which encode proteins homologous to the Drosophila 'sine oculis' homeobox protein. The encoded protein is a transcription factor which, like other members of this gene family, may be involved in limb or eye development. [provided by RefSeq, Dec 2008]

ENSG00000286728 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22175059).
• BS2: High AC in GnomAd4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016932.5. 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
	SIX2	NM_016932.5	MANE Select	c.707C>T	p.Pro236Leu	missense	Exon 2 of 2	NP_058628.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX2	ENST00000303077.7	TSL:1 MANE Select	c.707C>T	p.Pro236Leu	missense	Exon 2 of 2	ENSP00000304502.6	Q9NPC8
	SIX2	ENST00000933251.1		c.713C>T	p.Pro238Leu	missense	Exon 2 of 2	ENSP00000603310.1
	ENSG00000286728	ENST00000716438.1		n.161+3707G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000244 AC: 61 AN: 250282 AF XY: 0.000214

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000443

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000316 AC: 462 AN: 1461642 Hom.: 1 Cov.: 31 AF XY: 0.000316 AC XY: 230 AN XY: 727084

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

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

European-Non Finnish (NFE) AF: 0.000387 AC: 430 AN: 1111834

Other (OTH) AF: 0.000248 AC: 15 AN: 60378

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74372

African (AFR) AF: 0.0000724 AC: 3 AN: 41464

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital anomaly of kidney and urinary tract (1)
-	1	-	not provided (1)
-	1	-	SIX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.0055
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.33
Sift	Benign	0.27	T
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.24
MVP		0.71
MPC		0.022
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.069
gMVP		0.35
Mutation Taster		=80/20	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: rs372153489; hg19: chr2-45233478;